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Kauff, Noah

Positions:

Instructor, Temporary in the Obstetrics and Gynecology

Obstetrics and Gynecology, Gynecologic Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1993

M.D. — University of Pennsylvania

Grants:

Kastan Gray Foundation Project

Administered By
Duke Cancer Institute
AwardedBy
Gray Foundation
Role
Co Investigator
Start Date
October 01, 2017
End Date
September 30, 2019

Publications:

Observations on the origin of ovarian cortical inclusion cysts in women undergoing risk-reducing salpingo-oophorectomy.

Evidence suggests that up to 70% of high-grade serous ovarian carcinomas (HGSCs) arise potentially from fallopian tube fimbriae, and that many of the remaining cases arise from within the ovary in cortical inclusion cysts (CICs) with a Müllerian phenotype (Müllerian-CICs). It has been proposed that Müllerian-CICs arise either from metaplasia of mesothelial ovarian surface epithelium (OSE) entrapped within the ovary after ovulation or from normal tubal cells entrapped postovulation. However, this proposal is controversial. We therefore conducted a study of CICs in women, most of them BRCA1/2 mutation carriers, undergoing risk-reducing salpingo-oophorectomy at our institution from 2000 to 2014.We used immunohistochemistry for PAX8, a Müllerian marker, and calretinin, a mesothelial marker to classify CIC cells. In 499 CICs from 59 women, 72.3% were positive for PAX8 (PAX8+ ): ≥10% of CIC cells positive; 43.5% positive for calretinin (calretinin+ ). The proportion of PAX8+ CICs increased from 62.9% in premenopausal to 80.5% in postmenopausal patients. The proportion of calretinin+ CICs decreased from 52.6% to 35.6%, respectively. There was significant overlap of PAX8 and calretinin positivity: 82 (16.4%) CICs were PAX8+ /calretinin+ ; 43 (40.2%) of these 82 demonstrated PAX8+ /calretinin+ in the same cells.These results, and the increased ratio of PAX8+ to calretinin+ CICs from premenopausal to postmenopausal, show that many PAX8+ CICs probably arise from metaplasia of OSE-derived CICs. The proportion of PAX+ /calretinin- CICs arising from OSE-derived CICs is unclear, but our results strongly support the proposal that many Müllerian-CICs arise from OSE via metaplasia.

Authors
Park, KJ; Patel, P; Linkov, I; Jotwani, A; Kauff, N; Pike, MC
MLA Citation
Park, KJ, Patel, P, Linkov, I, Jotwani, A, Kauff, N, and Pike, MC. "Observations on the origin of ovarian cortical inclusion cysts in women undergoing risk-reducing salpingo-oophorectomy." Histopathology 72.5 (April 2018): 766-776.
PMID
29197096
Source
epmc
Published In
Histopathology
Volume
72
Issue
5
Publish Date
2018
Start Page
766
End Page
776
DOI
10.1111/his.13444

High-Grade Serous Ovarian Cancer: Associations between BRCA Mutation Status, CT Imaging Phenotypes, and Clinical Outcomes.

Purpose To investigate the associations between BRCA mutation status and computed tomography (CT) phenotypes of high-grade serous ovarian cancer (HGSOC) and to evaluate CT indicators of cytoreductive outcome and survival in patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 108 patients (33 with BRCA mutant and 75 with BRCA wild-type HGSOC) who underwent CT before primary debulking. Two radiologists independently reviewed the CT findings for various qualitative CT features. Associations between CT features, BRCA mutation status, cytoreductive outcome, and progression-free survival (PFS) were evaluated by using logistic regression and Cox proportional hazards regression, respectively. Results Peritoneal disease (PD) pattern, presence of PD in gastrohepatic ligament, mesenteric involvement, and supradiaphragmatic lymphadenopathy at CT were associated with BRCA mutation status (multiple regression: P < .001 for each CT feature). While clinical and CT features were not associated with cytoreductive outcome for patients with BRCA-mutant HGSOC, presence of PD in lesser sac (odds ratio [OR] = 2.40) and left upper quadrant (OR = 1.19), mesenteric involvement (OR = 7.10), and lymphadenopathy in supradiaphragmatic (OR = 2.83) and suprarenal para-aortic (OR = 4.79) regions were associated with higher odds of incomplete cytoreduction in BRCA wild-type HGSOC (multiple regression: P < .001 each CT feature). Mesenteric involvement at CT was associated with significantly shorter PFS for both patients with BRCA-mutant HGSOC (multiple regression: hazard ratio [HR] = 26.7 P < .001) and those with BRCA wild-type HGSOC (univariate analysis: reader 1, HR = 2.42, P < .001; reader 2, HR = 2.61; P < .001). Conclusion Qualitative CT features differed between patients with BRCA-mutant HGSOC and patients with BRCA wild-type HGSOC. CT indicators of cytoreductive outcome varied according to BRCA mutation status. Mesenteric involvement at CT was an indicator of significantly shorter PFS for both patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. © RSNA, 2017 Online supplemental material is available for this article.

Authors
Nougaret, S; Lakhman, Y; Gönen, M; Goldman, DA; Miccò, M; D'Anastasi, M; Johnson, SA; Juluru, K; Arnold, AG; Sosa, RE; Soslow, RA; Vargas, HA; Hricak, H; Kauff, ND; Sala, E
MLA Citation
Nougaret, S, Lakhman, Y, Gönen, M, Goldman, DA, Miccò, M, D'Anastasi, M, Johnson, SA, Juluru, K, Arnold, AG, Sosa, RE, Soslow, RA, Vargas, HA, Hricak, H, Kauff, ND, and Sala, E. "High-Grade Serous Ovarian Cancer: Associations between BRCA Mutation Status, CT Imaging Phenotypes, and Clinical Outcomes." Radiology 285.2 (November 2017): 472-481.
PMID
28628421
Source
epmc
Published In
Radiology
Volume
285
Issue
2
Publish Date
2017
Start Page
472
End Page
481
DOI
10.1148/radiol.2017161697

Cost Effectiveness of Risk-Reducing Mastectomy versus Surveillance in BRCA Mutation Carriers with a History of Ovarian Cancer.

The appropriate management of breast cancer risk in BRCA mutation carriers following ovarian cancer diagnosis remains unclear. We sought to determine the survival benefit and cost effectiveness of risk-reducing mastectomy (RRM) among women with BRCA1/2 mutations following stage II-IV ovarian cancer.We constructed a decision model from a third-party payer perspective to compare annual screening with magnetic resonance imaging (MRI) and mammography to annual screening followed by RRM with reconstruction following ovarian cancer diagnosis. Survival, overall costs, and cost effectiveness were determined by decade at diagnosis using 2015 US dollars. All inputs were obtained from the literature and public databases. Monte Carlo probabilistic sensitivity analysis was performed with a $100,000 willingness-to-pay threshold.The incremental cost-effectiveness ratio (ICER) per year of life saved (YLS) for RRM increased with age and BRCA2 mutation status, with greater survival benefit demonstrated in younger patients with BRCA1 mutations. RRM delayed 5 years in 40-year-old BRCA1 mutation carriers was associated with 5 months of life gained (ICER $72,739/YLS), and in 60-year-old BRCA2 mutation carriers was associated with 0.8 months of life gained (ICER $334,906/YLS). In all scenarios, $/YLS and mastectomies per breast cancer prevented were lowest with RRM performed 5-10 years after ovarian cancer diagnosis.For most BRCA1/2 mutation carriers following ovarian cancer diagnosis, RRM performed within 5 years is not cost effective when compared with breast cancer screening. Imaging surveillance should be advocated during the first several years after ovarian cancer diagnosis, after which point the benefits of RRM can be considered based on patient age and BRCA mutation status.

Authors
Gamble, C; Havrilesky, LJ; Myers, ER; Chino, JP; Hollenbeck, S; Plichta, JK; Kelly Marcom, P; Shelley Hwang, E; Kauff, ND; Greenup, RA
MLA Citation
Gamble, C, Havrilesky, LJ, Myers, ER, Chino, JP, Hollenbeck, S, Plichta, JK, Kelly Marcom, P, Shelley Hwang, E, Kauff, ND, and Greenup, RA. "Cost Effectiveness of Risk-Reducing Mastectomy versus Surveillance in BRCA Mutation Carriers with a History of Ovarian Cancer." Annals of Surgical Oncology 24.11 (October 2017): 3116-3123.
PMID
28699130
Source
epmc
Published In
Annals of Surgical Oncology
Volume
24
Issue
11
Publish Date
2017
Start Page
3116
End Page
3123
DOI
10.1245/s10434-017-5995-z

Adenoma Prevalence in Blacks and Whites Having Equal Adherence To Screening Colonoscopy: The National Colonoscopy Study.

Authors
Mendelsohn, RB; Winawer, SJ; Jammula, A; Mills, G; Jordan, P; O'Brien, MJ; Close, GM; Dorfman, M; Church, TR; Mandelson, MT; Allen, J; Feld, A; Kauff, ND; Morgan, GA; Kumar, JMR; Serrano, V; Bayuga-Miller, S; Fischer, SE; Kuk, D; Zauber, AG
MLA Citation
Mendelsohn, RB, Winawer, SJ, Jammula, A, Mills, G, Jordan, P, O'Brien, MJ, Close, GM, Dorfman, M, Church, TR, Mandelson, MT, Allen, J, Feld, A, Kauff, ND, Morgan, GA, Kumar, JMR, Serrano, V, Bayuga-Miller, S, Fischer, SE, Kuk, D, and Zauber, AG. "Adenoma Prevalence in Blacks and Whites Having Equal Adherence To Screening Colonoscopy: The National Colonoscopy Study." Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association 15.9 (September 2017): 1469-1470.
PMID
28419856
Source
epmc
Published In
Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association
Volume
15
Issue
9
Publish Date
2017
Start Page
1469
End Page
1470
DOI
10.1016/j.cgh.2017.04.014

Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing salpingo-oophorectomy for prophylaxis against serous/serous-like uterine cancers in BRCA1 mutation carriers.

To estimate the survival benefit and cost-effectiveness of performing hysterectomy during risk-reducing salpingo-oophorectomy (RRSO) for BRCA1 mutation carriers.Based on a recent prospective cohort study indicating an elevated incidence of serous/serous-like uterine cancers among BRCA1 mutation carriers, we constructed a modified Markov decision model from a payer perspective to inform decisions about performance of hysterectomy during RRSO at age 40. We assumed patients had previously undergone a risk-reducing mastectomy and had a residual risk of death from breast or ovarian cancer. Disease-specific survival, age-adjusted competing hysterectomy rates, and deaths from other causes were incorporated. Costs of risk-reducing surgery, competing hysterectomy, and care for serous/serous-like uterine cancer were included.A 40year old woman who undergoes RRSO+Hysterectomy gains 4.9 additional months of overall survival (40.38 versus 39.97 undiscounted years) compared to RRSO alone. The lifetime probabilities of developing or dying from serous/serous-like uterine cancer in the RRSO group are 3.5% and 2%, respectively. The RRSO alone strategy has an average cost of $9013 compared to $8803 for RRSO+Hysterectomy, and is dominated (less effective and more costly) when compared to RRSO+Hysterectomy. In an alternative analysis, delayed hysterectomy remains a cost-effective prevention strategy with an ICER of less than $100,000/year for up to 25years following RRSO at age 40.The addition of hysterectomy to RRSO in a 40year old BRCA1 mutation carrier results in a mean gain of 4.9 additional months of life and is cost-effective.

Authors
Havrilesky, LJ; Moss, HA; Chino, J; Myers, ER; Kauff, ND
MLA Citation
Havrilesky, LJ, Moss, HA, Chino, J, Myers, ER, and Kauff, ND. "Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing salpingo-oophorectomy for prophylaxis against serous/serous-like uterine cancers in BRCA1 mutation carriers." Gynecologic oncology 145.3 (June 2017): 549-554.
PMID
28390820
Source
epmc
Published In
Gynecologic Oncology
Volume
145
Issue
3
Publish Date
2017
Start Page
549
End Page
554
DOI
10.1016/j.ygyno.2017.03.025

Is There a Role for Ovarian Cancer Screening in High-Risk Women?

Authors
Berchuck, A; Havrilesky, LJ; Kauff, ND
MLA Citation
Berchuck, A, Havrilesky, LJ, and Kauff, ND. "Is There a Role for Ovarian Cancer Screening in High-Risk Women?." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 35.13 (May 2017): 1384-1386.
PMID
28447911
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
13
Publish Date
2017
Start Page
1384
End Page
1386
DOI
10.1200/jco.2016.72.0045

Reservations About Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations-Reply.

Authors
Shu, CA; Pike, MC; Kauff, ND
MLA Citation
Shu, CA, Pike, MC, and Kauff, ND. "Reservations About Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations-Reply." Jama Oncology 3.3 (March 2017): 417-418.
PMID
27832251
Source
epmc
Published In
Jama Oncology
Volume
3
Issue
3
Publish Date
2017
Start Page
417
End Page
418
DOI
10.1001/jamaoncol.2016.3900

Genetic/familial high-risk assessment: Breast and ovarian, version 2.2017: Featured updates to the NCCN guidelines

© JNCCN-Journal of the National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/ or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.

Authors
Daly, MB; Pilarski, R; Berry, M; Buys, SS; Farmer, M; Friedman, S; Garber, JE; Kauff, ND; Khan, S; Klein, C; Kohlmann, W; Kurian, A; Litton, JK; Madlensky, L; Merajver, SD; Offit, K; Pal, T; Reiser, G; Shannon, KM; Swisher, E; Vinayak, S; Voian, NC; Weitzel, JN; Wick, MJ; Wiesner, GL; Dwyer, M; Darlow, S
MLA Citation
Daly, MB, Pilarski, R, Berry, M, Buys, SS, Farmer, M, Friedman, S, Garber, JE, Kauff, ND, Khan, S, Klein, C, Kohlmann, W, Kurian, A, Litton, JK, Madlensky, L, Merajver, SD, Offit, K, Pal, T, Reiser, G, Shannon, KM, Swisher, E, Vinayak, S, Voian, NC, Weitzel, JN, Wick, MJ, Wiesner, GL, Dwyer, M, and Darlow, S. "Genetic/familial high-risk assessment: Breast and ovarian, version 2.2017: Featured updates to the NCCN guidelines." Jnccn Journal of the National Comprehensive Cancer Network 15.1 (January 1, 2017): 9-20. (Review)
Source
scopus
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
15
Issue
1
Publish Date
2017
Start Page
9
End Page
20

Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations.

The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial.To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy.This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression.Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database.Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors.Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.

Authors
Shu, CA; Pike, MC; Jotwani, AR; Friebel, TM; Soslow, RA; Levine, DA; Nathanson, KL; Konner, JA; Arnold, AG; Bogomolniy, F; Dao, F; Olvera, N; Bancroft, EK; Goldfrank, DJ; Stadler, ZK; Robson, ME; Brown, CL; Leitao, MM; Abu-Rustum, NR; Aghajanian, CA; Blum, JL; Neuhausen, SL; Garber, JE; Daly, MB; Isaacs, C; Eeles, RA; Ganz, PA; Barakat, RR; Offit, K; Domchek, SM; Rebbeck, TR; Kauff, ND
MLA Citation
Shu, CA, Pike, MC, Jotwani, AR, Friebel, TM, Soslow, RA, Levine, DA, Nathanson, KL, Konner, JA, Arnold, AG, Bogomolniy, F, Dao, F, Olvera, N, Bancroft, EK, Goldfrank, DJ, Stadler, ZK, Robson, ME, Brown, CL, Leitao, MM, Abu-Rustum, NR, Aghajanian, CA, Blum, JL, Neuhausen, SL, Garber, JE, Daly, MB, Isaacs, C, Eeles, RA, Ganz, PA, Barakat, RR, Offit, K, Domchek, SM, Rebbeck, TR, and Kauff, ND. "Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations." Jama Oncology 2.11 (November 2016): 1434-1440.
PMID
27367496
Source
epmc
Published In
Jama Oncology
Volume
2
Issue
11
Publish Date
2016
Start Page
1434
End Page
1440
DOI
10.1001/jamaoncol.2016.1820

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

OBJECTIVE:Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS:Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS:We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS:rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.

Authors
Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2, ; Hollestelle, A; van der Baan, FH; Berchuck, A; Johnatty, SE; Aben, KK; Agnarsson, BA; Aittomäki, K; Alducci, E; Andrulis, IL; Anton-Culver, H; Antonenkova, NN; Antoniou, AC; Apicella, C; Arndt, V; Arnold, N; Arun, BK; Arver, B; Ashworth, A; Australian Ovarian Cancer Study Group, ; Baglietto, L; Balleine, R; Bandera, EV; Barrowdale, D; Bean, YT; Beckmann, L; Beckmann, MW; Benitez, J; Berger, A; Berger, R; Beuselinck, B; Bisogna, M; Bjorge, L; Blomqvist, C; Bogdanova, NV; Bojesen, A; Bojesen, SE; Bolla, MK; Bonanni, B; Brand, JS; Brauch, H; Breast Cancer Family Register, ; Brenner, H; Brinton, L; Brooks-Wilson, A; Bruinsma, F; Brunet, J; Brüning, T; Budzilowska, A; Bunker, CH; Burwinkel, B; Butzow, R; Buys, SS; Caligo, MA; Campbell, I; Carter, J; Chang-Claude, J; Chanock, SJ; Claes, KBM; Collée, JM; Cook, LS; Couch, FJ; Cox, A; Cramer, D; Cross, SS; Cunningham, JM; Cybulski, C; Czene, K; Damiola, F; Dansonka-Mieszkowska, A; Darabi, H; de la Hoya, M; deFazio, A; Dennis, J; Devilee, P; Dicks, EM; Diez, O; Doherty, JA; Domchek, SM; Dorfling, CM; Dörk, T; Silva, IDS; du Bois, A; Dumont, M; Dunning, AM; Duran, M; Easton, DF; Eccles, D; Edwards, RP; Ehrencrona, H; Ejlertsen, B; Ekici, AB; Ellis, SD; EMBRACE, ; Engel, C; Eriksson, M; Fasching, PA; Feliubadalo, L; Figueroa, J; Flesch-Janys, D; Fletcher, O; Fontaine, A; Fortuzzi, S; Fostira, F; Fridley, BL; Friebel, T; Friedman, E; Friel, G; Frost, D; Garber, J; García-Closas, M; Gayther, SA; GEMO Study Collaborators, ; GENICA Network, ; Gentry-Maharaj, A; Gerdes, A-M; Giles, GG; Glasspool, R; Glendon, G; Godwin, AK; Goodman, MT; Gore, M; Greene, MH; Grip, M; Gronwald, J; Gschwantler Kaulich, D; Guénel, P; Guzman, SR; Haeberle, L; Haiman, CA; Hall, P; Halverson, SL; Hamann, U; Hansen, TVO; Harter, P; Hartikainen, JM; Healey, S; HEBON, ; Hein, A; Heitz, F; Henderson, BE; Herzog, J; T Hildebrandt, MA; Høgdall, CK; Høgdall, E; Hogervorst, FBL; Hopper, JL; Humphreys, K; Huzarski, T; Imyanitov, EN; Isaacs, C; Jakubowska, A; Janavicius, R; Jaworska, K; Jensen, A; Jensen, UB; Johnson, N; Jukkola-Vuorinen, A; Kabisch, M; Karlan, BY; Kataja, V; Kauff, N; KConFab Investigators, ; Kelemen, LE; Kerin, MJ; Kiemeney, LA; Kjaer, SK; Knight, JA; Knol-Bout, JP; Konstantopoulou, I; Kosma, V-M; Krakstad, C; Kristensen, V; Kuchenbaecker, KB; Kupryjanczyk, J; Laitman, Y; Lambrechts, D; Lambrechts, S; Larson, MC; Lasa, A; Laurent-Puig, P; Lazaro, C; Le, ND; Le Marchand, L; Leminen, A; Lester, J; Levine, DA; Li, J; Liang, D; Lindblom, A; Lindor, N; Lissowska, J; Long, J; Lu, KH; Lubinski, J; Lundvall, L; Lurie, G; Mai, PL; Mannermaa, A; Margolin, S; Mariette, F; Marme, F; Martens, JWM; Massuger, LFAG; Maugard, C; Mazoyer, S; McGuffog, L; McGuire, V; McLean, C; McNeish, I; Meindl, A; Menegaux, F; Menéndez, P; Menkiszak, J; Menon, U; Mensenkamp, AR; Miller, N; Milne, RL; Modugno, F; Montagna, M; Moysich, KB; Müller, H; Mulligan, AM; Muranen, TA; Narod, SA; Nathanson, KL; Ness, RB; Neuhausen, SL; Nevanlinna, H; Neven, P; Nielsen, FC; Nielsen, SF; Nordestgaard, BG; Nussbaum, RL; Odunsi, K; Offit, K; Olah, E; Olopade, OI; Olson, JE; Olson, SH; Oosterwijk, JC; Orlow, I; Orr, N; Orsulic, S; Osorio, A; Ottini, L; Paul, J; Pearce, CL; Pedersen, IS; Peissel, B; Pejovic, T; Pelttari, LM; Perkins, J; Permuth-Wey, J; Peterlongo, P; Peto, J; Phelan, CM; Phillips, K-A; Piedmonte, M; Pike, MC; Platte, R; Plisiecka-Halasa, J; Poole, EM; Poppe, B; Pylkäs, K; Radice, P; Ramus, SJ; Rebbeck, TR; Reed, MWR; Rennert, G; Risch, HA; Robson, M; Rodriguez, GC; Romero, A; Rossing, MA; Rothstein, JH; Rudolph, A; Runnebaum, I; Salani, R; Salvesen, HB; Sawyer, EJ; Schildkraut, JM; Schmidt, MK; Schmutzler, RK; Schneeweiss, A; Schoemaker, MJ; Schrauder, MG; Schumacher, F; Schwaab, I; Scuvera, G; Sellers, TA; Severi, G; Seynaeve, CM; Shah, M; Shrubsole, M; Siddiqui, N; Sieh, W; Simard, J; Singer, CF; Sinilnikova, OM; Smeets, D; Sohn, C; Soller, M; Song, H; Soucy, P; Southey, MC; Stegmaier, C; Stoppa-Lyonnet, D; Sucheston, L; SWE-BRCA, ; Swerdlow, A; Tangen, IL; Tea, M-K; Teixeira, MR; Terry, KL; Terry, MB; Thomassen, M; Thompson, PJ; Tihomirova, L; Tischkowitz, M; Toland, AE; Tollenaar, RAEM; Tomlinson, I; Torres, D; Truong, T; Tsimiklis, H; Tung, N; Tworoger, SS; Tyrer, JP; Vachon, CM; Van 't Veer, LJ; van Altena, AM; Van Asperen, CJ; van den Berg, D; van den Ouweland, AMW; van Doorn, HC; Van Nieuwenhuysen, E; van Rensburg, EJ; Vergote, I; Verhoef, S; Vierkant, RA; Vijai, J; Vitonis, AF; von Wachenfeldt, A; Walsh, C; Wang, Q; Wang-Gohrke, S; Wappenschmidt, B; Weischer, M; Weitzel, JN; Weltens, C; Wentzensen, N; Whittemore, AS; Wilkens, LR; Winqvist, R; Wu, AH; Wu, X; Yang, HP; Zaffaroni, D; Pilar Zamora, M; Zheng, W; Ziogas, A; Chenevix-Trench, G; Pharoah, PDP; Rookus, MA; Hooning, MJ; Goode, EL
MLA Citation
Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2, , Hollestelle, A, van der Baan, FH, Berchuck, A, Johnatty, SE, Aben, KK, Agnarsson, BA, Aittomäki, K, Alducci, E, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Antoniou, AC, Apicella, C, Arndt, V, Arnold, N, Arun, BK, Arver, B, Ashworth, A, Australian Ovarian Cancer Study Group, , Baglietto, L, Balleine, R, Bandera, EV, Barrowdale, D, Bean, YT, Beckmann, L, Beckmann, MW, Benitez, J, Berger, A, Berger, R, Beuselinck, B, Bisogna, M, Bjorge, L, Blomqvist, C, Bogdanova, NV, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Brand, JS, Brauch, H, Breast Cancer Family Register, , Brenner, H, Brinton, L, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Brüning, T, Budzilowska, A, Bunker, CH, Burwinkel, B, Butzow, R, Buys, SS, Caligo, MA, Campbell, I, Carter, J, Chang-Claude, J, Chanock, SJ, Claes, KBM, Collée, JM, Cook, LS, Couch, FJ, Cox, A, Cramer, D, Cross, SS, Cunningham, JM, Cybulski, C, Czene, K, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, de la Hoya, M, deFazio, A, Dennis, J, Devilee, P, Dicks, EM, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Silva, IDS, du Bois, A, Dumont, M, Dunning, AM, Duran, M, Easton, DF, Eccles, D, Edwards, RP, Ehrencrona, H, Ejlertsen, B, Ekici, AB, Ellis, SD, EMBRACE, , Engel, C, Eriksson, M, Fasching, PA, Feliubadalo, L, Figueroa, J, Flesch-Janys, D, Fletcher, O, Fontaine, A, Fortuzzi, S, Fostira, F, Fridley, BL, Friebel, T, Friedman, E, Friel, G, Frost, D, Garber, J, García-Closas, M, Gayther, SA, GEMO Study Collaborators, , GENICA Network, , Gentry-Maharaj, A, Gerdes, A-M, Giles, GG, Glasspool, R, Glendon, G, Godwin, AK, Goodman, MT, Gore, M, Greene, MH, Grip, M, Gronwald, J, Gschwantler Kaulich, D, Guénel, P, Guzman, SR, Haeberle, L, Haiman, CA, Hall, P, Halverson, SL, Hamann, U, Hansen, TVO, Harter, P, Hartikainen, JM, Healey, S, HEBON, , Hein, A, Heitz, F, Henderson, BE, Herzog, J, T Hildebrandt, MA, Høgdall, CK, Høgdall, E, Hogervorst, FBL, Hopper, JL, Humphreys, K, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, Janavicius, R, Jaworska, K, Jensen, A, Jensen, UB, Johnson, N, Jukkola-Vuorinen, A, Kabisch, M, Karlan, BY, Kataja, V, Kauff, N, KConFab Investigators, , Kelemen, LE, Kerin, MJ, Kiemeney, LA, Kjaer, SK, Knight, JA, Knol-Bout, JP, Konstantopoulou, I, Kosma, V-M, Krakstad, C, Kristensen, V, Kuchenbaecker, KB, Kupryjanczyk, J, Laitman, Y, Lambrechts, D, Lambrechts, S, Larson, MC, Lasa, A, Laurent-Puig, P, Lazaro, C, Le, ND, Le Marchand, L, Leminen, A, Lester, J, Levine, DA, Li, J, Liang, D, Lindblom, A, Lindor, N, Lissowska, J, Long, J, Lu, KH, Lubinski, J, Lundvall, L, Lurie, G, Mai, PL, Mannermaa, A, Margolin, S, Mariette, F, Marme, F, Martens, JWM, Massuger, LFAG, Maugard, C, Mazoyer, S, McGuffog, L, McGuire, V, McLean, C, McNeish, I, Meindl, A, Menegaux, F, Menéndez, P, Menkiszak, J, Menon, U, Mensenkamp, AR, Miller, N, Milne, RL, Modugno, F, Montagna, M, Moysich, KB, Müller, H, Mulligan, AM, Muranen, TA, Narod, SA, Nathanson, KL, Ness, RB, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, FC, Nielsen, SF, Nordestgaard, BG, Nussbaum, RL, Odunsi, K, Offit, K, Olah, E, Olopade, OI, Olson, JE, Olson, SH, Oosterwijk, JC, Orlow, I, Orr, N, Orsulic, S, Osorio, A, Ottini, L, Paul, J, Pearce, CL, Pedersen, IS, Peissel, B, Pejovic, T, Pelttari, LM, Perkins, J, Permuth-Wey, J, Peterlongo, P, Peto, J, Phelan, CM, Phillips, K-A, Piedmonte, M, Pike, MC, Platte, R, Plisiecka-Halasa, J, Poole, EM, Poppe, B, Pylkäs, K, Radice, P, Ramus, SJ, Rebbeck, TR, Reed, MWR, Rennert, G, Risch, HA, Robson, M, Rodriguez, GC, Romero, A, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, I, Salani, R, Salvesen, HB, Sawyer, EJ, Schildkraut, JM, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schrauder, MG, Schumacher, F, Schwaab, I, Scuvera, G, Sellers, TA, Severi, G, Seynaeve, CM, Shah, M, Shrubsole, M, Siddiqui, N, Sieh, W, Simard, J, Singer, CF, Sinilnikova, OM, Smeets, D, Sohn, C, Soller, M, Song, H, Soucy, P, Southey, MC, Stegmaier, C, Stoppa-Lyonnet, D, Sucheston, L, SWE-BRCA, , Swerdlow, A, Tangen, IL, Tea, M-K, Teixeira, MR, Terry, KL, Terry, MB, Thomassen, M, Thompson, PJ, Tihomirova, L, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Tsimiklis, H, Tung, N, Tworoger, SS, Tyrer, JP, Vachon, CM, Van 't Veer, LJ, van Altena, AM, Van Asperen, CJ, van den Berg, D, van den Ouweland, AMW, van Doorn, HC, Van Nieuwenhuysen, E, van Rensburg, EJ, Vergote, I, Verhoef, S, Vierkant, RA, Vijai, J, Vitonis, AF, von Wachenfeldt, A, Walsh, C, Wang, Q, Wang-Gohrke, S, Wappenschmidt, B, Weischer, M, Weitzel, JN, Weltens, C, Wentzensen, N, Whittemore, AS, Wilkens, LR, Winqvist, R, Wu, AH, Wu, X, Yang, HP, Zaffaroni, D, Pilar Zamora, M, Zheng, W, Ziogas, A, Chenevix-Trench, G, Pharoah, PDP, Rookus, MA, Hooning, MJ, and Goode, EL. "No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer." Gynecologic Oncology 141.2 (May 2016): 386-401. (Review)
PMID
25940428
Source
epmc
Published In
Gynecologic Oncology
Volume
141
Issue
2
Publish Date
2016
Start Page
386
End Page
401
DOI
10.1016/j.ygyno.2015.04.034

Genome Sequencing of Multiple Primary Tumors Reveals a Novel PALB2 Variant.

Authors
Schrader, KA; Stratton, KL; Murali, R; Laitman, Y; Cavallone, L; Offit, L; Wen, YH; Thomas, T; Shah, S; Rau-Murthy, R; Manschreck, C; Salo-Mullen, E; Otegbeye, E; Corines, M; Zhang, L; Norton, L; Hudis, C; Klein, RJ; Kauff, ND; Robson, M; Stadler, ZK; Haber, DA; Lipkin, SM; Friedman, E; Foulkes, WD; Altshuler, D; Vijai, J; Offit, K
MLA Citation
Schrader, KA, Stratton, KL, Murali, R, Laitman, Y, Cavallone, L, Offit, L, Wen, YH, Thomas, T, Shah, S, Rau-Murthy, R, Manschreck, C, Salo-Mullen, E, Otegbeye, E, Corines, M, Zhang, L, Norton, L, Hudis, C, Klein, RJ, Kauff, ND, Robson, M, Stadler, ZK, Haber, DA, Lipkin, SM, Friedman, E, Foulkes, WD, Altshuler, D, Vijai, J, and Offit, K. "Genome Sequencing of Multiple Primary Tumors Reveals a Novel PALB2 Variant." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 34.8 (March 2016): e61-e67.
PMID
24982446
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
8
Publish Date
2016
Start Page
e61
End Page
e67
DOI
10.1200/jco.2013.50.0272

Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.

To evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.A matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer.Genetic clinics.Detailed information regarding treatment of infertility was collected from a routinely administered questionnaire.None.Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment.There was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18-2.33) and the subsequent risk of ovarian cancer.Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation.

Authors
Gronwald, J; Glass, K; Rosen, B; Karlan, B; Tung, N; Neuhausen, SL; Moller, P; Ainsworth, P; Sun, P; Narod, SA; Lubinski, J; Kotsopoulos, J; Hereditary Breast Cancer Clinical Study Group,
MLA Citation
Gronwald, J, Glass, K, Rosen, B, Karlan, B, Tung, N, Neuhausen, SL, Moller, P, Ainsworth, P, Sun, P, Narod, SA, Lubinski, J, Kotsopoulos, J, and Hereditary Breast Cancer Clinical Study Group, . "Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation." Fertility and Sterility 105.3 (March 2016): 781-785.
PMID
26698676
Source
epmc
Published In
Fertility and Sterility
Volume
105
Issue
3
Publish Date
2016
Start Page
781
End Page
785
DOI
10.1016/j.fertnstert.2015.11.034

Invasion Patterns of Metastatic Extrauterine High-grade Serous Carcinoma With BRCA Germline Mutation and Correlation With Clinical Outcomes.

Characteristic histopathologic features have been described in high-grade serous carcinoma associated with BRCA abnormalities (HGSC-BRCA), which are known to have relatively favorable clinical outcomes. The aim of this study was to evaluate the clinical significance of invasion patterns in metastatic HGSC-BRCA cases. Of the 37 cases of advanced-stage HGSC with known BRCA1 or BRCA2 germline mutation retrieved from our institutional files, 23 patients had a germline mutation of BRCA1 and 14 had a BRCA2 mutation. The pattern of invasion at metastatic sites was recorded and classified as a pushing pattern (either predominantly or exclusively), an exclusively micropapillary infiltrative pattern, or an infiltrative pattern composed of papillae, micropapillae, glands, and nests (mixed infiltrative pattern). Histologic evaluation of metastases was performed without knowledge of genotype or clinical outcome. Clinical data were abstracted from medical records. Median age was 56 years (range, 31 to 73 y). All patients presented at stage IIIC or IV and underwent complete surgical staging followed by chemotherapy. All 37 HGSC-BRCA cases showed either pushing pattern metastases (30; 81%) or infiltrative micropapillary metastases (7; 19%). No HGSC-BRCA case exhibited metastases composed solely of mixed infiltrative patterns. Among the 7 infiltrative micropapillary cases, 6 had a BRCA1 germline mutation versus 1 with a BRCA2 mutation. The median time of follow-up was 26 months (range, 13 to 49 mo). All 7 patients with infiltrative micropapillary metastases either experienced recurrence or died of disease (5 recurrences and 2 deaths), which was significantly worse than what was seen in patients with predominantly pushing pattern metastases, of whom 16 of 30 (53%) experienced recurrence (n=14) or died of disease (n=2) (P=0.03). In conclusion, the recognition of different invasion patterns of metastatic extrauterine HGSC-BRCA has prognostic implications. The infiltrative micropapillary pattern is associated with poor outcomes and is more frequently seen in BRCA1-associated HGSC than in BRCA2 cases.

Authors
Hussein, YR; Ducie, JA; Arnold, AG; Kauff, ND; Vargas-Alvarez, HA; Sala, E; Levine, DA; Soslow, RA
MLA Citation
Hussein, YR, Ducie, JA, Arnold, AG, Kauff, ND, Vargas-Alvarez, HA, Sala, E, Levine, DA, and Soslow, RA. "Invasion Patterns of Metastatic Extrauterine High-grade Serous Carcinoma With BRCA Germline Mutation and Correlation With Clinical Outcomes." The American Journal of Surgical Pathology 40.3 (March 2016): 404-409.
PMID
26574845
Source
epmc
Published In
The American Journal of Surgical Pathology
Volume
40
Issue
3
Publish Date
2016
Start Page
404
End Page
409
DOI
10.1097/pas.0000000000000556

RE: Breast Cancer Risk After Salpingo-Oophorectomy in Healthy BRCA1/2 Mutation Carriers: Revisiting the Evidence for Risk Reduction.

Authors
Chai, X; Domchek, S; Kauff, N; Rebbeck, T; Chen, J
MLA Citation
Chai, X, Domchek, S, Kauff, N, Rebbeck, T, and Chen, J. "RE: Breast Cancer Risk After Salpingo-Oophorectomy in Healthy BRCA1/2 Mutation Carriers: Revisiting the Evidence for Risk Reduction." Journal of the National Cancer Institute 107.9 (September 2015). (Letter)
PMID
26264690
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
107
Issue
9
Publish Date
2015
DOI
10.1093/jnci/djv217

Breast cancer: oophorectomy for BRCA1 ER--negative disease-an open debate.

Authors
Kauff, N; Robson, M
MLA Citation
Kauff, N, and Robson, M. "Breast cancer: oophorectomy for BRCA1 ER--negative disease-an open debate." Nature Reviews. Clinical Oncology 12.9 (September 2015): 505-506.
PMID
26196251
Source
epmc
Published In
Nature Reviews. Clinical Oncology
Volume
12
Issue
9
Publish Date
2015
Start Page
505
End Page
506
DOI
10.1038/nrclinonc.2015.130

Development and validation of a clinical score for predicting risk of adenoma at screening colonoscopy.

Currently, no clinical tools use demographic and risk factor information to predict the risk of finding an adenoma in individuals undergoing colon cancer screening. Such a tool would be valuable for identifying those who would most benefit from screening colonoscopy.We used baseline data from men and women who underwent screening colonoscopy from the randomized, multicenter National Colonoscopy Study (NCS) to develop and validate an adenoma risk model. The study, conducted at three sites in the United States (Minneapolis, MN; Seattle, WA; and Shreveport, LA) asked all participants to complete baseline questionnaires on clinical risk factors and family history. Model parameters estimated from logistic regression yielded an area under the receiver operating characteristic curve (AUROCC) used to assess prediction.Five hundred forty-one subjects were included in the development model, and 1,334 in the validation of the risk score. Variables in the prediction of adenoma risk for colonoscopy screening were age (likelihood ratio test for overall contribution to model, P < 0.001), male sex (P < 0.001), body mass index (P < 0.001), family history of at least one first-degree relative with colorectal cancer (P = 0.036), and smoking history (P < 0.001). The adjusted AUROCC of 0.67 [95% confidence interval (CI), 0.61-0.74] for the derivation cohort was not statistically significantly different from that in the validation cohort. The adjusted AUROCC for the entire cohort was 0.64 (95% CI, 0.60-0.67).We developed and validated a simple well-calibrated risk score.This tool may be useful for estimating risk of adenomas in screening eligible men and women.

Authors
Shaukat, A; Church, TR; Shanley, R; Kauff, ND; O'Brien, MJ; Mills, GM; Jordan, PA; Allen, JA; Kim, A; Feld, AD; Zauber, AG; Winawer, SJ
MLA Citation
Shaukat, A, Church, TR, Shanley, R, Kauff, ND, O'Brien, MJ, Mills, GM, Jordan, PA, Allen, JA, Kim, A, Feld, AD, Zauber, AG, and Winawer, SJ. "Development and validation of a clinical score for predicting risk of adenoma at screening colonoscopy." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 24.6 (June 2015): 913-920.
PMID
25800242
Source
epmc
Published In
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
Volume
24
Issue
6
Publish Date
2015
Start Page
913
End Page
920
DOI
10.1158/1055-9965.epi-14-1321

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Authors
Rebbeck, TR; Mitra, N; Wan, F; Sinilnikova, OM; Healey, S; McGuffog, L; Mazoyer, S; Chenevix-Trench, G; Easton, DF; Antoniou, AC; Nathanson, KL; CIMBA Consortium, ; Laitman, Y; Kushnir, A; Paluch-Shimon, S; Berger, R; Zidan, J; Friedman, E; Ehrencrona, H; Stenmark-Askmalm, M; Einbeigi, Z; Loman, N; Harbst, K; Rantala, J; Melin, B; Huo, D; Olopade, OI; Seldon, J; Ganz, PA; Nussbaum, RL; Chan, SB; Odunsi, K; Gayther, SA; Domchek, SM; Arun, BK; Lu, KH; Mitchell, G; Karlan, BY; Walsh, C; Lester, J; Godwin, AK; Pathak, H; Ross, E; Daly, MB; Whittemore, AS; John, EM; Miron, A; Terry, MB; Chung, WK; Goldgar, DE; Buys, SS; Janavicius, R; Tihomirova, L; Tung, N; Dorfling, CM; van Rensburg, EJ; Steele, L; Neuhausen, SL; Ding, YC; Ejlertsen, B; Gerdes, A-M; Hansen, TVO; Ramón y Cajal, T; Osorio, A; Benitez, J; Godino, J; Tejada, M-I; Duran, M; Weitzel, JN; Bobolis, KA; Sand, SR; Fontaine, A; Savarese, A; Pasini, B; Peissel, B; Bonanni, B; Zaffaroni, D; Vignolo-Lutati, F; Scuvera, G; Giannini, G; Bernard, L; Genuardi, M; Radice, P; Dolcetti, R; Manoukian, S; Pensotti, V; Gismondi, V; Yannoukakos, D; Fostira, F; Garber, J; Torres, D; Rashid, MU; Hamann, U; Peock, S; Frost, D; Platte, R; Evans, DG; Eeles, R; Davidson, R; Eccles, D; Cole, T; Cook, J; Brewer, C; Hodgson, S; Morrison, PJ; Walker, L; Porteous, ME; Kennedy, MJ; Izatt, L; Adlard, J; Donaldson, A; Ellis, S; Sharma, P; Schmutzler, RK; Wappenschmidt, B; Becker, A; Rhiem, K; Hahnen, E; Engel, C; Meindl, A; Engert, S; Ditsch, N; Arnold, N; Plendl, HJ; Mundhenke, C; Niederacher, D; Fleisch, M; Sutter, C; Bartram, CR; Dikow, N; Wang-Gohrke, S; Gadzicki, D; Steinemann, D; Kast, K; Beer, M; Varon-Mateeva, R; Gehrig, A; Weber, BH; Stoppa-Lyonnet, D; Houdayer, C; Belotti, M; Gauthier-Villars, M; Damiola, F; Boutry-Kryza, N; Lasset, C; Sobol, H; Peyrat, J-P; Muller, D; Fricker, J-P; Collonge-Rame, M-A; Mortemousque, I; Nogues, C; Rouleau, E; Isaacs, C; De Paepe, A; Poppe, B; Claes, K; De Leeneer, K; Piedmonte, M; Rodriguez, G; Wakely, K; Boggess, J; Blank, SV; Basil, J; Azodi, M; Phillips, K-A; Caldes, T; de la Hoya, M; Romero, A; Nevanlinna, H; Aittomäki, K; van der Hout, AH; Hogervorst, FBL; Verhoef, S; Collée, JM; Seynaeve, C; Oosterwijk, JC; Gille, JJP; Wijnen, JT; Gómez Garcia, EB; Kets, CM; Ausems, MGEM; Aalfs, CM; Devilee, P; Mensenkamp, AR; Kwong, A; Olah, E; Papp, J; Diez, O; Lazaro, C; Darder, E; Blanco, I; Salinas, M; Jakubowska, A; Lubinski, J; Gronwald, J; Jaworska-Bieniek, K; Durda, K; Sukiennicki, G; Huzarski, T; Byrski, T; Cybulski, C; Toloczko-Grabarek, A; Złowocka-Perłowska, E; Menkiszak, J; Arason, A; Barkardottir, RB; Simard, J; Laframboise, R; Montagna, M; Agata, S; Alducci, E; Peixoto, A; Teixeira, MR; Spurdle, AB; Lee, MH; Park, SK; Kim, S-W; Friebel, TM; Couch, FJ; Lindor, NM; Pankratz, VS; Guidugli, L; Wang, X; Tischkowitz, M; Foretova, L; Vijai, J; Offit, K; Robson, M; Rau-Murthy, R; Kauff, N; Fink-Retter, A; Singer, CF; Rappaport, C; Gschwantler-Kaulich, D; Pfeiler, G; Tea, M-K; Berger, A; Greene, MH; Mai, PL; Imyanitov, EN; Toland, AE; Senter, L; Bojesen, A; Pedersen, IS; Skytte, A-B; Sunde, L; Thomassen, M; Moeller, ST; Kruse, TA; Jensen, UB; Caligo, MA; Aretini, P; Teo, S-H; Selkirk, CG; Hulick, PJ; Andrulis, I
MLA Citation
Rebbeck, TR, Mitra, N, Wan, F, Sinilnikova, OM, Healey, S, McGuffog, L, Mazoyer, S, Chenevix-Trench, G, Easton, DF, Antoniou, AC, Nathanson, KL, CIMBA Consortium, , Laitman, Y, Kushnir, A, Paluch-Shimon, S, Berger, R, Zidan, J, Friedman, E, Ehrencrona, H, Stenmark-Askmalm, M, Einbeigi, Z, Loman, N, Harbst, K, Rantala, J, Melin, B, Huo, D, Olopade, OI, Seldon, J, Ganz, PA, Nussbaum, RL, Chan, SB, Odunsi, K, Gayther, SA, Domchek, SM, Arun, BK, Lu, KH, Mitchell, G, Karlan, BY, Walsh, C, Lester, J, Godwin, AK, Pathak, H, Ross, E, Daly, MB, Whittemore, AS, John, EM, Miron, A, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Steele, L, Neuhausen, SL, Ding, YC, Ejlertsen, B, Gerdes, A-M, Hansen, TVO, Ramón y Cajal, T, Osorio, A, Benitez, J, Godino, J, Tejada, M-I, Duran, M, Weitzel, JN, Bobolis, KA, Sand, SR, Fontaine, A, Savarese, A, Pasini, B, Peissel, B, Bonanni, B, Zaffaroni, D, Vignolo-Lutati, F, Scuvera, G, Giannini, G, Bernard, L, Genuardi, M, Radice, P, Dolcetti, R, Manoukian, S, Pensotti, V, Gismondi, V, Yannoukakos, D, Fostira, F, Garber, J, Torres, D, Rashid, MU, Hamann, U, Peock, S, Frost, D, Platte, R, Evans, DG, Eeles, R, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Porteous, ME, Kennedy, MJ, Izatt, L, Adlard, J, Donaldson, A, Ellis, S, Sharma, P, Schmutzler, RK, Wappenschmidt, B, Becker, A, Rhiem, K, Hahnen, E, Engel, C, Meindl, A, Engert, S, Ditsch, N, Arnold, N, Plendl, HJ, Mundhenke, C, Niederacher, D, Fleisch, M, Sutter, C, Bartram, CR, Dikow, N, Wang-Gohrke, S, Gadzicki, D, Steinemann, D, Kast, K, Beer, M, Varon-Mateeva, R, Gehrig, A, Weber, BH, Stoppa-Lyonnet, D, Houdayer, C, Belotti, M, Gauthier-Villars, M, Damiola, F, Boutry-Kryza, N, Lasset, C, Sobol, H, Peyrat, J-P, Muller, D, Fricker, J-P, Collonge-Rame, M-A, Mortemousque, I, Nogues, C, Rouleau, E, Isaacs, C, De Paepe, A, Poppe, B, Claes, K, De Leeneer, K, Piedmonte, M, Rodriguez, G, Wakely, K, Boggess, J, Blank, SV, Basil, J, Azodi, M, Phillips, K-A, Caldes, T, de la Hoya, M, Romero, A, Nevanlinna, H, Aittomäki, K, van der Hout, AH, Hogervorst, FBL, Verhoef, S, Collée, JM, Seynaeve, C, Oosterwijk, JC, Gille, JJP, Wijnen, JT, Gómez Garcia, EB, Kets, CM, Ausems, MGEM, Aalfs, CM, Devilee, P, Mensenkamp, AR, Kwong, A, Olah, E, Papp, J, Diez, O, Lazaro, C, Darder, E, Blanco, I, Salinas, M, Jakubowska, A, Lubinski, J, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Sukiennicki, G, Huzarski, T, Byrski, T, Cybulski, C, Toloczko-Grabarek, A, Złowocka-Perłowska, E, Menkiszak, J, Arason, A, Barkardottir, RB, Simard, J, Laframboise, R, Montagna, M, Agata, S, Alducci, E, Peixoto, A, Teixeira, MR, Spurdle, AB, Lee, MH, Park, SK, Kim, S-W, Friebel, TM, Couch, FJ, Lindor, NM, Pankratz, VS, Guidugli, L, Wang, X, Tischkowitz, M, Foretova, L, Vijai, J, Offit, K, Robson, M, Rau-Murthy, R, Kauff, N, Fink-Retter, A, Singer, CF, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Berger, A, Greene, MH, Mai, PL, Imyanitov, EN, Toland, AE, Senter, L, Bojesen, A, Pedersen, IS, Skytte, A-B, Sunde, L, Thomassen, M, Moeller, ST, Kruse, TA, Jensen, UB, Caligo, MA, Aretini, P, Teo, S-H, Selkirk, CG, Hulick, PJ, and Andrulis, I. "Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer." Jama 313.13 (April 2015): 1347-1361.
PMID
25849179
Source
epmc
Published In
Jama
Volume
313
Issue
13
Publish Date
2015
Start Page
1347
End Page
1361
DOI
10.1001/jama.2014.5985

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Authors
Kuchenbaecker, KB; Ramus, SJ; Tyrer, J; Lee, A; Shen, HC; Beesley, J; Lawrenson, K; McGuffog, L; Healey, S; Lee, JM; Spindler, TJ; Lin, YG; Pejovic, T; Bean, Y; Li, Q; Coetzee, S; Hazelett, D; Miron, A; Southey, M; Terry, MB; Goldgar, DE; Buys, SS; Janavicius, R; Dorfling, CM; van Rensburg, EJ; Neuhausen, SL; Ding, YC; Hansen, TVO; Jønson, L; Gerdes, A-M; Ejlertsen, B; Barrowdale, D; Dennis, J; Benitez, J; Osorio, A; Garcia, MJ; Komenaka, I; Weitzel, JN; Ganschow, P; Peterlongo, P; Bernard, L; Viel, A; Bonanni, B; Peissel, B; Manoukian, S; Radice, P; Papi, L; Ottini, L; Fostira, F; Konstantopoulou, I; Garber, J; Frost, D; Perkins, J; Platte, R; Ellis, S; EMBRACE, ; Godwin, AK; Schmutzler, RK; Meindl, A; Engel, C; Sutter, C; Sinilnikova, OM; GEMO Study Collaborators, ; Damiola, F; Mazoyer, S; Stoppa-Lyonnet, D; Claes, K; De Leeneer, K; Kirk, J; Rodriguez, GC; Piedmonte, M; O'Malley, DM; de la Hoya, M; Caldes, T; Aittomäki, K; Nevanlinna, H; Collée, JM; Rookus, MA; Oosterwijk, JC; Breast Cancer Family Registry, ; Tihomirova, L; Tung, N; Hamann, U; Isaccs, C; Tischkowitz, M; Imyanitov, EN; Caligo, MA; Campbell, IG; Hogervorst, FBL; HEBON, ; Olah, E; Diez, O; Blanco, I; Brunet, J; Lazaro, C; Pujana, MA; Jakubowska, A; Gronwald, J; Lubinski, J; Sukiennicki, G; Barkardottir, RB; Plante, M; Simard, J; Soucy, P; Montagna, M; Tognazzo, S; Teixeira, MR; KConFab Investigators, ; Pankratz, VS; Wang, X; Lindor, N; Szabo, CI; Kauff, N; Vijai, J; Aghajanian, CA; Pfeiler, G; Berger, A; Singer, CF; Tea, M-K; Phelan, CM; Greene, MH; Mai, PL; Rennert, G; Mulligan, AM; Tchatchou, S; Andrulis, IL; Glendon, G; Toland, AE; Jensen, UB; Kruse, TA; Thomassen, M; Bojesen, A; Zidan, J; Friedman, E; Laitman, Y; Soller, M; Liljegren, A; Arver, B; Einbeigi, Z; Stenmark-Askmalm, M; Olopade, OI; Nussbaum, RL; Rebbeck, TR; Nathanson, KL; Domchek, SM; Lu, KH; Karlan, BY; Walsh, C; Lester, J; Australian Cancer Study (Ovarian Cancer Investigators), ; Australian Ovarian Cancer Study Group, ; Hein, A; Ekici, AB; Beckmann, MW; Fasching, PA; Lambrechts, D; Van Nieuwenhuysen, E; Vergote, I; Lambrechts, S; Dicks, E; Doherty, JA; Wicklund, KG; Rossing, MA; Rudolph, A; Chang-Claude, J; Wang-Gohrke, S; Eilber, U; Moysich, KB; Odunsi, K; Sucheston, L; Lele, S; Wilkens, LR; Goodman, MT; Thompson, PJ; Shvetsov, YB; Runnebaum, IB; Dürst, M; Hillemanns, P; Dörk, T; Antonenkova, N; Bogdanova, N; Leminen, A; Pelttari, LM; Butzow, R; Modugno, F; Kelley, JL; Edwards, RP; Ness, RB; du Bois, A; Heitz, F; Schwaab, I; Harter, P; Matsuo, K; Hosono, S; Orsulic, S; Jensen, A; Kjaer, SK; Hogdall, E; Hasmad, HN; Azmi, MAN; Teo, S-H; Woo, Y-L; Fridley, BL; Goode, EL; Cunningham, JM; Vierkant, RA; Bruinsma, F; Giles, GG; Liang, D; Hildebrandt, MAT; Wu, X; Levine, DA; Bisogna, M; Berchuck, A; Iversen, ES; Schildkraut, JM; Concannon, P; Weber, RP; Cramer, DW; Terry, KL; Poole, EM; Tworoger, SS; Bandera, EV; Orlow, I; Olson, SH; Krakstad, C; Salvesen, HB; Tangen, IL; Bjorge, L; van Altena, AM; Aben, KKH; Kiemeney, LA; Massuger, LFAG; Kellar, M; Brooks-Wilson, A; Kelemen, LE; Cook, LS; Le, ND; Cybulski, C; Yang, H; Lissowska, J; Brinton, LA; Wentzensen, N; Hogdall, C; Lundvall, L; Nedergaard, L; Baker, H; Song, H; Eccles, D; McNeish, I; Paul, J; Carty, K; Siddiqui, N; Glasspool, R; Whittemore, AS; Rothstein, JH; McGuire, V; Sieh, W; Ji, B-T; Zheng, W; Shu, X-O; Gao, Y-T; Rosen, B; Risch, HA; McLaughlin, JR; Narod, SA; Monteiro, AN; Chen, A; Lin, H-Y; Permuth-Wey, J; Sellers, TA; Tsai, Y-Y; Chen, Z; Ziogas, A; Anton-Culver, H; Gentry-Maharaj, A; Menon, U; Harrington, P; Lee, AW; Wu, AH; Pearce, CL; Coetzee, G; Pike, MC; Dansonka-Mieszkowska, A; Timorek, A; Rzepecka, IK; Kupryjanczyk, J; Freedman, M; Noushmehr, H; Easton, DF; Offit, K; Couch, FJ; Gayther, S; Pharoah, PP; Antoniou, AC; Chenevix-Trench, G; Consortium of Investigators of Modifiers of BRCA1 and BRCA2,
MLA Citation
Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jønson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, EMBRACE, , Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, GEMO Study Collaborators, , Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomäki, K, Nevanlinna, H, Collée, JM, Rookus, MA, Oosterwijk, JC, Breast Cancer Family Registry, , Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, HEBON, , Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaro, C, Pujana, MA, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, KConFab Investigators, , Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Australian Cancer Study (Ovarian Cancer Investigators), , Australian Ovarian Cancer Study Group, , Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, Chenevix-Trench, G, and Consortium of Investigators of Modifiers of BRCA1 and BRCA2, . "Identification of six new susceptibility loci for invasive epithelial ovarian cancer." Nature Genetics 47.2 (February 2015): 164-171.
PMID
25581431
Source
epmc
Published In
Nature Genetics
Volume
47
Issue
2
Publish Date
2015
Start Page
164
End Page
171
DOI
10.1038/ng.3185

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Authors
Blanco, I; Kuchenbaecker, K; Cuadras, D; Wang, X; Barrowdale, D; de Garibay, GR; Librado, P; Sánchez-Gracia, A; Rozas, J; Bonifaci, N; McGuffog, L; Pankratz, VS; Islam, A; Mateo, F; Berenguer, A; Petit, A; Català, I; Brunet, J; Feliubadaló, L; Tornero, E; Benítez, J; Osorio, A; Ramón y Cajal, T; Nevanlinna, H; Aittomäki, K; Arun, BK; Toland, AE; Karlan, BY; Walsh, C; Lester, J; Greene, MH; Mai, PL; Nussbaum, RL; Andrulis, IL; Domchek, SM; Nathanson, KL; Rebbeck, TR; Barkardottir, RB; Jakubowska, A; Lubinski, J; Durda, K; Jaworska-Bieniek, K; Claes, K; Van Maerken, T; Díez, O; Hansen, TV; Jønson, L; Gerdes, A-M; Ejlertsen, B; de la Hoya, M; Caldés, T; Dunning, AM; Oliver, C; Fineberg, E; Cook, M; Peock, S; McCann, E; Murray, A; Jacobs, C; Pichert, G; Lalloo, F; Chu, C; Dorkins, H; Paterson, J; Ong, K-R; Teixeira, MR; Teixeira, ; Hogervorst, FBL; van der Hout, AH; Seynaeve, C; van der Luijt, RB; Ligtenberg, MJL; Devilee, P; Wijnen, JT; Rookus, MA; Meijers-Heijboer, HEJ; Blok, MJ; van den Ouweland, AMW; Aalfs, CM; Rodriguez, GC; Phillips, K-AA; Piedmonte, M; Nerenstone, SR; Bae-Jump, VL; O'Malley, DM; Ratner, ES; Schmutzler, RK; Wappenschmidt, B; Rhiem, K; Engel, C; Meindl, A; Ditsch, N; Arnold, N; Plendl, HJ; Niederacher, D; Sutter, C; Wang-Gohrke, S; Steinemann, D; Preisler-Adams, S; Kast, K; Varon-Mateeva, R; Gehrig, A; Bojesen, A; Pedersen, IS; Sunde, L; Jensen, UB; Thomassen, M; Kruse, TA; Foretova, L; Peterlongo, P; Bernard, L; Peissel, B; Scuvera, G; Manoukian, S; Radice, P; Ottini, L; Montagna, M; Agata, S; Maugard, C; Simard, J; Soucy, P; Berger, A; Fink-Retter, A; Singer, CF; Rappaport, C; Geschwantler-Kaulich, D; Tea, M-K; Pfeiler, G; BCFR, ; John, EM; Miron, A; Neuhausen, SL; Terry, MB; Chung, WK; Daly, MB; Goldgar, DE; Janavicius, R; Dorfling, CM; van Rensburg, EJ; Fostira, F; Konstantopoulou, I; Garber, J; Godwin, AK; Olah, E; Narod, SA; Rennert, G; Paluch, SS; Laitman, Y; Friedman, E; SWE-BRCA, ; Liljegren, A; Rantala, J; Stenmark-Askmalm, M; Loman, N; Imyanitov, EN; Hamann, U; kConFab Investigators, ; Spurdle, AB; Healey, S; Weitzel, JN; Herzog, J; Margileth, D; Gorrini, C; Esteller, M; Gómez, A; Sayols, S; Vidal, E; Heyn, H; GEMO, ; Stoppa-Lyonnet, D; Léoné, M; Barjhoux, L; Fassy-Colcombet, M; de Pauw, A; Lasset, C; Ferrer, SF; Castera, L; Berthet, P; Cornelis, F; Bignon, Y-J; Damiola, F; Mazoyer, S; Sinilnikova, OM; Maxwell, CA; Vijai, J; Robson, M; Kauff, N; Corines, MJ; Villano, D; Cunningham, J; Lee, A; Lindor, N; Lázaro, C; Easton, DF; Offit, K; Chenevix-Trench, G; Couch, FJ; Antoniou, AC; Pujana, MA
MLA Citation
Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, X, Barrowdale, D, de Garibay, GR, Librado, P, Sánchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Català, I, Brunet, J, Feliubadaló, L, Tornero, E, Benítez, J, Osorio, A, Ramón y Cajal, T, Nevanlinna, H, Aittomäki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Díez, O, Hansen, TV, Jønson, L, Gerdes, A-M, Ejlertsen, B, de la Hoya, M, Caldés, T, Dunning, AM, Oliver, C, Fineberg, E, Cook, M, Peock, S, McCann, E, Murray, A, Jacobs, C, Pichert, G, Lalloo, F, Chu, C, Dorkins, H, Paterson, J, Ong, K-R, Teixeira, MR, Teixeira, , Hogervorst, FBL, van der Hout, AH, Seynaeve, C, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, AMW, Aalfs, CM, Rodriguez, GC, Phillips, K-AA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, M, Kruse, TA, Foretova, L, Peterlongo, P, Bernard, L, Peissel, B, Scuvera, G, Manoukian, S, Radice, P, Ottini, L, Montagna, M, Agata, S, Maugard, C, Simard, J, Soucy, P, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, M-K, Pfeiler, G, BCFR, , John, EM, Miron, A, Neuhausen, SL, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, SWE-BRCA, , Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Loman, N, Imyanitov, EN, Hamann, U, kConFab Investigators, , Spurdle, AB, Healey, S, Weitzel, JN, Herzog, J, Margileth, D, Gorrini, C, Esteller, M, Gómez, A, Sayols, S, Vidal, E, Heyn, H, GEMO, , Stoppa-Lyonnet, D, Léoné, M, Barjhoux, L, Fassy-Colcombet, M, de Pauw, A, Lasset, C, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, Y-J, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, Lee, A, Lindor, N, Lázaro, C, Easton, DF, Offit, K, Chenevix-Trench, G, Couch, FJ, Antoniou, AC, and Pujana, MA. "Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers." Plos One 10.4 (January 2015): e0120020-null.
PMID
25830658
Source
epmc
Published In
Plos One
Volume
10
Issue
4
Publish Date
2015
Start Page
e0120020
DOI
10.1371/journal.pone.0120020

The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.

BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms.Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups.Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92).BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.

Authors
Meisel, JL; Hyman, DM; Garg, K; Zhou, Q; Dao, F; Bisogna, M; Gao, J; Schultz, ND; Grisham, RN; Phillips, M; Iasonos, A; Kauff, ND; Levine, DA; Soslow, RA; Spriggs, DR
MLA Citation
Meisel, JL, Hyman, DM, Garg, K, Zhou, Q, Dao, F, Bisogna, M, Gao, J, Schultz, ND, Grisham, RN, Phillips, M, Iasonos, A, Kauff, ND, Levine, DA, Soslow, RA, and Spriggs, DR. "The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer." Annals of Oncology : Official Journal of the European Society for Medical Oncology 25.12 (December 2014): 2372-2378.
PMID
25281711
Source
epmc
Published In
Annals of Oncology
Volume
25
Issue
12
Publish Date
2014
Start Page
2372
End Page
2378
DOI
10.1093/annonc/mdu461

Invasion patterns of metastatic high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency.

High-grade serous carcinomas of the uterine adnexa with BRCA1 deficiency (high-grade serous carcinomas-BRCA) have recently been described to demonstrate characteristic histopathological features. We hypothesize that metastatic high-grade serous carcinomas-BRCA cases exhibit characteristic morphological features as well. We studied 102 high-grade serous carcinomas with known BRCA1 and BRCA2 genotype from the archives of the Department of Pathology at Memorial Sloan-Kettering Cancer Center. The primary site morphological characteristics of these cases were reported previously; we now focus solely on tumor morphology in sites other than the uterine adnexa (ie, metastatic sites). The study group consisted of the following case types: 13 BRCA1 germline mutations; 5 BRCA1 somatic mutations; 10 BRCA1 promoter methylation; 4 BRCA2 germline mutations; 1 BRCA2 somatic mutation; 11 lacking BRCA1 or BRCA2 abnormality; 58 cases lacking BRCA1 or BRCA2 germline mutation. Two observers independently scored invasion patterns and microscopic tumor architecture while blinded to genotype. Concordance between observers and correlations between metastatic patterns and the following indices were studied: genotype, primary site tumor characteristics, and BRCA1 immunohistochemistry. Concordance between observers was excellent (κ values >0.9). All cases with BRCA1 or 2 abnormalities showed either pushing pattern metastases (76%) or infiltrative metastases composed only of micropapillae (24%). In contrast, all cases lacking BRCA1 or 2 abnormalities showed infiltrative metastases that contained combinations of papillary, glandular, and, rarely, cribriform and micropapillary architecture (P<0.0001 for comparison with pushing metastasis and P<0.001 for comparison with purely micropapillary architecture). Morphological assessment of metastatic carcinomas, a highly reproducible exercise, accurately correlated with BRCA1 status in every case, unlike morphological assessment of primary site adnexal high-grade serous carcinomas or BRCA1 immunohistochemistry. Metastatic high-grade serous carcinomas-BRCAs exhibit characteristic morphological features that appear more sensitive and specific for BRCA mutations than two other morphologically based prediction systems and should be easier to apply in practice. These findings should be validated prospectively in an independent cohort.

Authors
Reyes, MC; Arnold, AG; Kauff, ND; Levine, DA; Soslow, RA
MLA Citation
Reyes, MC, Arnold, AG, Kauff, ND, Levine, DA, and Soslow, RA. "Invasion patterns of metastatic high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency." Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc 27.10 (October 2014): 1405-1411.
PMID
24577588
Source
epmc
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
27
Issue
10
Publish Date
2014
Start Page
1405
End Page
1411
DOI
10.1038/modpathol.2013.237

Pathologic findings at risk-reducing salpingo-oophorectomy: primary results from Gynecologic Oncology Group Trial GOG-0199.

Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study.This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression.Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign.Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.

Authors
Sherman, ME; Piedmonte, M; Mai, PL; Ioffe, OB; Ronnett, BM; Van Le, L; Ivanov, I; Bell, MC; Blank, SV; DiSilvestro, P; Hamilton, CA; Tewari, KS; Wakeley, K; Kauff, ND; Yamada, SD; Rodriguez, G; Skates, SJ; Alberts, DS; Walker, JL; Minasian, L; Lu, K; Greene, MH
MLA Citation
Sherman, ME, Piedmonte, M, Mai, PL, Ioffe, OB, Ronnett, BM, Van Le, L, Ivanov, I, Bell, MC, Blank, SV, DiSilvestro, P, Hamilton, CA, Tewari, KS, Wakeley, K, Kauff, ND, Yamada, SD, Rodriguez, G, Skates, SJ, Alberts, DS, Walker, JL, Minasian, L, Lu, K, and Greene, MH. "Pathologic findings at risk-reducing salpingo-oophorectomy: primary results from Gynecologic Oncology Group Trial GOG-0199." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 32.29 (October 2014): 3275-3283.
PMID
25199754
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
29
Publish Date
2014
Start Page
3275
End Page
3283
DOI
10.1200/JCO.2013.54.1987

Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

Authors
Gronwald, J; Robidoux, A; Kim-Sing, C; Tung, N; Lynch, HT; Foulkes, WD; Manoukian, S; Ainsworth, P; Neuhausen, SL; Demsky, R; Eisen, A; Singer, CF; Saal, H; Senter, L; Eng, C; Weitzel, J; Moller, P; Gilchrist, DM; Olopade, O; Ginsburg, O; Sun, P; Huzarski, T; Lubinski, J; Narod, SA; Hereditary Breast Cancer Clinical Study Group,
MLA Citation
Gronwald, J, Robidoux, A, Kim-Sing, C, Tung, N, Lynch, HT, Foulkes, WD, Manoukian, S, Ainsworth, P, Neuhausen, SL, Demsky, R, Eisen, A, Singer, CF, Saal, H, Senter, L, Eng, C, Weitzel, J, Moller, P, Gilchrist, DM, Olopade, O, Ginsburg, O, Sun, P, Huzarski, T, Lubinski, J, Narod, SA, and Hereditary Breast Cancer Clinical Study Group, . "Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers." Breast Cancer Research and Treatment 146.2 (July 2014): 421-427.
PMID
24951267
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
146
Issue
2
Publish Date
2014
Start Page
421
End Page
427
DOI
10.1007/s10549-014-3026-3

Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families.

BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis.

Authors
Arnold, AG; Otegbeye, E; Fleischut, MH; Glogowski, EA; Siegel, B; Boyar, SR; Salo-Mullen, E; Amoroso, K; Sheehan, M; Berliner, JL; Stadler, ZK; Kauff, ND; Offit, K; Robson, ME; Zhang, L
MLA Citation
Arnold, AG, Otegbeye, E, Fleischut, MH, Glogowski, EA, Siegel, B, Boyar, SR, Salo-Mullen, E, Amoroso, K, Sheehan, M, Berliner, JL, Stadler, ZK, Kauff, ND, Offit, K, Robson, ME, and Zhang, L. "Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families." Breast Cancer Research and Treatment 145.3 (June 2014): 625-634.
PMID
24825132
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
145
Issue
3
Publish Date
2014
Start Page
625
End Page
634
DOI
10.1007/s10549-014-2987-6

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Authors
Osorio, A; Milne, RL; Kuchenbaecker, K; Vaclová, T; Pita, G; Alonso, R; Peterlongo, P; Blanco, I; de la Hoya, M; Duran, M; Díez, O; Ramón Y Cajal, T; Konstantopoulou, I; Martínez-Bouzas, C; Andrés Conejero, R; Soucy, P; McGuffog, L; Barrowdale, D; Lee, A; Swe-Brca, ; Arver, B; Rantala, J; Loman, N; Ehrencrona, H; Olopade, OI; Beattie, MS; Domchek, SM; Nathanson, K; Rebbeck, TR; Arun, BK; Karlan, BY; Walsh, C; Lester, J; John, EM; Whittemore, AS; Daly, MB; Southey, M; Hopper, J; Terry, MB; Buys, SS; Janavicius, R; Dorfling, CM; van Rensburg, EJ; Steele, L; Neuhausen, SL; Ding, YC; Hansen, TVO; Jønson, L; Ejlertsen, B; Gerdes, A-M; Infante, M; Herráez, B; Moreno, LT; Weitzel, JN; Herzog, J; Weeman, K; Manoukian, S; Peissel, B; Zaffaroni, D; Scuvera, G; Bonanni, B; Mariette, F; Volorio, S; Viel, A; Varesco, L; Papi, L; Ottini, L; Tibiletti, MG; Radice, P; Yannoukakos, D; Garber, J; Ellis, S; Frost, D; Platte, R; Fineberg, E; Evans, G; Lalloo, F; Izatt, L; Eeles, R; Adlard, J; Davidson, R; Cole, T; Eccles, D; Cook, J; Hodgson, S; Brewer, C; Tischkowitz, M; Douglas, F; Porteous, M; Side, L; Walker, L; Morrison, P; Donaldson, A; Kennedy, J; Foo, C; Godwin, AK; Schmutzler, RK; Wappenschmidt, B; Rhiem, K; Engel, C; Meindl, A; Ditsch, N; Arnold, N; Plendl, HJ; Niederacher, D; Sutter, C; Wang-Gohrke, S; Steinemann, D; Preisler-Adams, S; Kast, K; Varon-Mateeva, R; Gehrig, A; Stoppa-Lyonnet, D; Sinilnikova, OM; Mazoyer, S; Damiola, F; Poppe, B; Claes, K; Piedmonte, M; Tucker, K; Backes, F; Rodríguez, G; Brewster, W; Wakeley, K; Rutherford, T; Caldés, T; Nevanlinna, H; Aittomäki, K; Rookus, MA; van Os, TAM; van der Kolk, L; de Lange, JL; Meijers-Heijboer, HEJ; van der Hout, AH; van Asperen, CJ; Gómez Garcia, EB; Hoogerbrugge, N; Collée, JM; van Deurzen, CHM; van der Luijt, RB; Devilee, P; Hebon, ; Olah, E; Lázaro, C; Teulé, A; Menéndez, M; Jakubowska, A; Cybulski, C; Gronwald, J; Lubinski, J; Durda, K; Jaworska-Bieniek, K; Johannsson, OT; Maugard, C; Montagna, M; Tognazzo, S; Teixeira, MR; Healey, S; Investigators, K; Olswold, C; Guidugli, L; Lindor, N; Slager, S; Szabo, CI; Vijai, J; Robson, M; Kauff, N; Zhang, L; Rau-Murthy, R; Fink-Retter, A; Singer, CF; Rappaport, C; Geschwantler Kaulich, D; Pfeiler, G; Tea, M-K; Berger, A; Phelan, CM; Greene, MH; Mai, PL; Lejbkowicz, F; Andrulis, I; Mulligan, AM; Glendon, G; Toland, AE; Bojesen, A; Pedersen, IS; Sunde, L; Thomassen, M; Kruse, TA; Jensen, UB; Friedman, E; Laitman, Y; Shimon, SP; Simard, J; Easton, DF; Offit, K; Couch, FJ; Chenevix-Trench, G; Antoniou, AC; Benitez, J
MLA Citation
Osorio, A, Milne, RL, Kuchenbaecker, K, Vaclová, T, Pita, G, Alonso, R, Peterlongo, P, Blanco, I, de la Hoya, M, Duran, M, Díez, O, Ramón Y Cajal, T, Konstantopoulou, I, Martínez-Bouzas, C, Andrés Conejero, R, Soucy, P, McGuffog, L, Barrowdale, D, Lee, A, Swe-Brca, , Arver, B, Rantala, J, Loman, N, Ehrencrona, H, Olopade, OI, Beattie, MS, Domchek, SM, Nathanson, K, Rebbeck, TR, Arun, BK, Karlan, BY, Walsh, C, Lester, J, John, EM, Whittemore, AS, Daly, MB, Southey, M, Hopper, J, Terry, MB, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Steele, L, Neuhausen, SL, Ding, YC, Hansen, TVO, Jønson, L, Ejlertsen, B, Gerdes, A-M, Infante, M, Herráez, B, Moreno, LT, Weitzel, JN, Herzog, J, Weeman, K, Manoukian, S, Peissel, B, Zaffaroni, D, Scuvera, G, Bonanni, B, Mariette, F, Volorio, S, Viel, A, Varesco, L, Papi, L, Ottini, L, Tibiletti, MG, Radice, P, Yannoukakos, D, Garber, J, Ellis, S, Frost, D, Platte, R, Fineberg, E, Evans, G, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Cole, T, Eccles, D, Cook, J, Hodgson, S, Brewer, C, Tischkowitz, M, Douglas, F, Porteous, M, Side, L, Walker, L, Morrison, P, Donaldson, A, Kennedy, J, Foo, C, Godwin, AK, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Damiola, F, Poppe, B, Claes, K, Piedmonte, M, Tucker, K, Backes, F, Rodríguez, G, Brewster, W, Wakeley, K, Rutherford, T, Caldés, T, Nevanlinna, H, Aittomäki, K, Rookus, MA, van Os, TAM, van der Kolk, L, de Lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, van Asperen, CJ, Gómez Garcia, EB, Hoogerbrugge, N, Collée, JM, van Deurzen, CHM, van der Luijt, RB, Devilee, P, Hebon, , Olah, E, Lázaro, C, Teulé, A, Menéndez, M, Jakubowska, A, Cybulski, C, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Johannsson, OT, Maugard, C, Montagna, M, Tognazzo, S, Teixeira, MR, Healey, S, Investigators, K, Olswold, C, Guidugli, L, Lindor, N, Slager, S, Szabo, CI, Vijai, J, Robson, M, Kauff, N, Zhang, L, Rau-Murthy, R, Fink-Retter, A, Singer, CF, Rappaport, C, Geschwantler Kaulich, D, Pfeiler, G, Tea, M-K, Berger, A, Phelan, CM, Greene, MH, Mai, PL, Lejbkowicz, F, Andrulis, I, Mulligan, AM, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Sunde, L, Thomassen, M, Kruse, TA, Jensen, UB, Friedman, E, Laitman, Y, Shimon, SP, Simard, J, Easton, DF, Offit, K, Couch, FJ, Chenevix-Trench, G, Antoniou, AC, and Benitez, J. "DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers." Plos Genetics 10.4 (April 3, 2014): e1004256-null.
PMID
24698998
Source
epmc
Published In
Plos Genetics
Volume
10
Issue
4
Publish Date
2014
Start Page
e1004256
DOI
10.1371/journal.pgen.1004256

American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.

Authors
Lu, KH; Wood, ME; Daniels, M; Burke, C; Ford, J; Kauff, ND; Kohlmann, W; Lindor, NM; Mulvey, TM; Robinson, L; Rubinstein, WS; Stoffel, EM; Snyder, C; Syngal, S; Merrill, JK; Wollins, DS; Hughes, KS; American Society of Clinical Oncology,
MLA Citation
Lu, KH, Wood, ME, Daniels, M, Burke, C, Ford, J, Kauff, ND, Kohlmann, W, Lindor, NM, Mulvey, TM, Robinson, L, Rubinstein, WS, Stoffel, EM, Snyder, C, Syngal, S, Merrill, JK, Wollins, DS, Hughes, KS, and American Society of Clinical Oncology, . "American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 32.8 (March 2014): 833-840.
PMID
24493721
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
8
Publish Date
2014
Start Page
833
End Page
840
DOI
10.1200/JCO.2013.50.9257

Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC).

OBJECTIVE:Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC. MATERIALS/METHODS:We retrospectively reviewed the medical records of consecutive patients with a germline BRCA1/2 mutation or a high-risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients had peritoneal washings collected. All surgical specimens were assessed using the sectioning and extensively examining the fimbria protocol, with immunohistochemistry when indicated. p53 signature lesions and secretory cell outgrowths were excluded. RESULTS:Of 593 patients who underwent RRSO, isolated STIC was diagnosed in 12 patients (2%). Five patients (42%) were BRCA1 positive, 5 patients (42%) were BRCA2 positive, and 2 patients (17%) had high-risk family history. Preoperatively, all patients with STIC had normal CA-125 levels and/or pelvic imaging results. Seven patients underwent hysterectomy and omentectomy, 6 patients (46%) had pelvic node dissections, and 5 patients (39%) had para-aortic node dissections. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 28 months (range, 16-44 months), no recurrences have been identified. CONCLUSIONS:Among the cases of isolated STIC after RRSO reported in the literature, the yield of surgical staging is low, and short-term clinical outcomes are favorable. Peritoneal washings are the most common site of disease spread. Individualized management is warranted until additional data become available.

Authors
Wethington, SL; Park, KJ; Soslow, RA; Kauff, ND; Brown, CL; Dao, F; Otegbeye, E; Sonoda, Y; Abu-Rustum, NR; Barakat, RR; Levine, DA; Gardner, GJ
MLA Citation
Wethington, SL, Park, KJ, Soslow, RA, Kauff, ND, Brown, CL, Dao, F, Otegbeye, E, Sonoda, Y, Abu-Rustum, NR, Barakat, RR, Levine, DA, and Gardner, GJ. "Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC)." International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society 23.9 (November 2013): 1603-1611.
PMID
24172097
Source
epmc
Published In
International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society
Volume
23
Issue
9
Publish Date
2013
Start Page
1603
End Page
1611
DOI
10.1097/igc.0b013e3182a80ac8

Hereditary gynecologic cancers

Authors
Lu, KH; Berchuck, A; Kauff, ND
MLA Citation
Lu, KH, Berchuck, A, and Kauff, ND. "Hereditary gynecologic cancers." Principles and Practice of Gynecologic Oncology: Sixth Edition. May 8, 2013. 60-69.
Source
scopus
Publish Date
2013
Start Page
60
End Page
69

Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer.

BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC.

Authors
Domchek, SM; Jhaveri, K; Patil, S; Stopfer, JE; Hudis, C; Powers, J; Stadler, Z; Goldstein, L; Kauff, N; Khasraw, M; Offit, K; Nathanson, KL; Robson, M
MLA Citation
Domchek, SM, Jhaveri, K, Patil, S, Stopfer, JE, Hudis, C, Powers, J, Stadler, Z, Goldstein, L, Kauff, N, Khasraw, M, Offit, K, Nathanson, KL, and Robson, M. "Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer." Cancer 119.7 (April 2013): 1344-1348.
PMID
23165893
Source
epmc
Published In
Cancer
Volume
119
Issue
7
Publish Date
2013
Start Page
1344
End Page
1348
DOI
10.1002/cncr.27842

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Authors
Couch, FJ; Wang, X; McGuffog, L; Lee, A; Olswold, C; Kuchenbaecker, KB; Soucy, P; Fredericksen, Z; Barrowdale, D; Dennis, J; Gaudet, MM; Dicks, E; Kosel, M; Healey, S; Sinilnikova, OM; Lee, A; Bacot, F; Vincent, D; Hogervorst, FBL; Peock, S; Stoppa-Lyonnet, D; Jakubowska, A; kConFab Investigators, ; Radice, P; Schmutzler, RK; SWE-BRCA, ; Domchek, SM; Piedmonte, M; Singer, CF; Friedman, E; Thomassen, M; Ontario Cancer Genetics Network, ; Hansen, TVO; Neuhausen, SL; Szabo, CI; Blanco, I; Greene, MH; Karlan, BY; Garber, J; Phelan, CM; Weitzel, JN; Montagna, M; Olah, E; Andrulis, IL; Godwin, AK; Yannoukakos, D; Goldgar, DE; Caldes, T; Nevanlinna, H; Osorio, A; Terry, MB; Daly, MB; van Rensburg, EJ; Hamann, U; Ramus, SJ; Toland, AE; Caligo, MA; Olopade, OI; Tung, N; Claes, K; Beattie, MS; Southey, MC; Imyanitov, EN; Tischkowitz, M; Janavicius, R; John, EM; Kwong, A; Diez, O; Balmaña, J; Barkardottir, RB; Arun, BK; Rennert, G; Teo, S-H; Ganz, PA; Campbell, I; van der Hout, AH; van Deurzen, CHM; Seynaeve, C; Gómez Garcia, EB; van Leeuwen, FE; Meijers-Heijboer, HEJ; Gille, JJP; Ausems, MGEM; Blok, MJ; Ligtenberg, MJL; Rookus, MA; Devilee, P; Verhoef, S; van Os, TAM; Wijnen, JT; HEBON, ; EMBRACE, ; Frost, D; Ellis, S; Fineberg, E; Platte, R; Evans, DG; Izatt, L; Eeles, RA; Adlard, J; Eccles, DM; Cook, J; Brewer, C; Douglas, F; Hodgson, S; Morrison, PJ; Side, LE; Donaldson, A; Houghton, C; Rogers, MT; Dorkins, H; Eason, J; Gregory, H; McCann, E; Murray, A; Calender, A; Hardouin, A; Berthet, P; Delnatte, C; Nogues, C; Lasset, C; Houdayer, C; Leroux, D; Rouleau, E; Prieur, F; Damiola, F; Sobol, H; Coupier, I; Venat-Bouvet, L; Castera, L; Gauthier-Villars, M; Léoné, M; Pujol, P; Mazoyer, S; Bignon, Y-J; GEMO Study Collaborators, ; Złowocka-Perłowska, E; Gronwald, J; Lubinski, J; Durda, K; Jaworska, K; Huzarski, T; Spurdle, AB; Viel, A; Peissel, B; Bonanni, B; Melloni, G; Ottini, L; Papi, L; Varesco, L; Tibiletti, MG; Peterlongo, P; Volorio, S; Manoukian, S; Pensotti, V; Arnold, N; Engel, C; Deissler, H; Gadzicki, D; Gehrig, A; Kast, K; Rhiem, K; Meindl, A; Niederacher, D; Ditsch, N; Plendl, H; Preisler-Adams, S; Engert, S; Sutter, C; Varon-Mateeva, R; Wappenschmidt, B; Weber, BHF; Arver, B; Stenmark-Askmalm, M; Loman, N; Rosenquist, R; Einbeigi, Z; Nathanson, KL; Rebbeck, TR; Blank, SV; Cohn, DE; Rodriguez, GC; Small, L; Friedlander, M; Bae-Jump, VL; Fink-Retter, A; Rappaport, C; Gschwantler-Kaulich, D; Pfeiler, G; Tea, M-K; Lindor, NM; Kaufman, B; Shimon Paluch, S; Laitman, Y; Skytte, A-B; Gerdes, A-M; Pedersen, IS; Moeller, ST; Kruse, TA; Jensen, UB; Vijai, J; Sarrel, K; Robson, M; Kauff, N; Mulligan, AM; Glendon, G; Ozcelik, H; Ejlertsen, B; Nielsen, FC; Jønson, L; Andersen, MK; Ding, YC; Steele, L; Foretova, L; Teulé, A; Lazaro, C; Brunet, J; Pujana, MA; Mai, PL; Loud, JT; Walsh, C; Lester, J; Orsulic, S; Narod, SA; Herzog, J; Sand, SR; Tognazzo, S; Agata, S; Vaszko, T; Weaver, J; Stavropoulou, AV; Buys, SS; Romero, A; de la Hoya, M; Aittomäki, K; Muranen, TA; Duran, M; Chung, WK; Lasa, A; Dorfling, CM; Miron, A; BCFR, ; Benitez, J; Senter, L; Huo, D; Chan, SB; Sokolenko, AP; Chiquette, J; Tihomirova, L; Friebel, TM; Agnarsson, BA; Lu, KH; Lejbkowicz, F; James, PA; Hall, P; Dunning, AM; Tessier, D; Cunningham, J; Slager, SL; Wang, C; Hart, S; Stevens, K; Simard, J; Pastinen, T; Pankratz, VS; Offit, K; Easton, DF; Chenevix-Trench, G; Antoniou, AC; CIMBA,
MLA Citation
Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Lee, A, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, kConFab Investigators, , Radice, P, Schmutzler, RK, SWE-BRCA, , Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Ontario Cancer Genetics Network, , Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmaña, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Gómez Garcia, EB, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, HEBON, , EMBRACE, , Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Léoné, M, Pujol, P, Mazoyer, S, Bignon, Y-J, GEMO Study Collaborators, , Złowocka-Perłowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Shimon Paluch, S, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jønson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teulé, A, Lazaro, C, Brunet, J, Pujana, MA, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomäki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, BCFR, , Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and CIMBA, . "Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk." Plos Genetics 9.3 (January 2013): e1003212-null.
PMID
23544013
Source
epmc
Published In
Plos Genetics
Volume
9
Issue
3
Publish Date
2013
Start Page
e1003212
DOI
10.1371/journal.pgen.1003212

Screening for familial ovarian cancer: a ray of hope and a light to steer by.

Authors
Long, KC; Kauff, ND
MLA Citation
Long, KC, and Kauff, ND. "Screening for familial ovarian cancer: a ray of hope and a light to steer by." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 31.1 (January 2013): 8-10.
PMID
23213103
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
1
Publish Date
2013
Start Page
8
End Page
10
DOI
10.1200/jco.2012.45.4678

Incorporating information regarding preimplantation genetic diagnosis into discussions concerning testing and risk management for BRCA1/2 mutations: a qualitative study of patient preferences.

Studies have shown that BRCA1/2 mutation carriers are interested in learning about reproductive options such as preimplantation genetic diagnosis (PGD) to prevent passing their risk onto their children. However, attitudes vary widely, and the procedure raises complex ethical and psychosocial issues. This complexity, plus the highly technical nature of PGD, makes it difficult to integrate PGD information into genetic counseling sessions that already cover probabilistic, emotionally charged risk information.A total of 33 carriers of the BRCA1/2 mutation who were of reproductive age and had previously undergone genetic counseling viewed a tutorial regarding PGD and were interviewed concerning their attitudes toward PGD and preferences about how to include PGD information in genetic counseling.The majority of participants preferred to be briefly informed of the availability of PGD information, and to receive written materials regarding PGD, but with the option of deferring detailed discussion if they already believed themselves to be overloaded or perceived that PGD was not immediately relevant to their risk management and/or childbearing plans. For some individuals, the stress of testing temporarily interfered with information processing, producing states of cognitive avoidance ("in a fog," or "tuning out"). Some preferred to discuss PGD with a physician with whom they had an ongoing relationship (eg, obstetrician/gynecologist, primary care provider, or oncologist).Providers offering cancer genetic testing may consider indicating the availability of PGD information to their patients, while attending to the patients' level of interest and ability to absorb information. Research is needed to link patient responses to information overload with psychosocial outcomes (eg, distress, and quality of decision-making). Continuing medical education is needed to support providers in facilitating informed decisions regarding PGD.

Authors
Hurley, K; Rubin, LR; Werner-Lin, A; Sagi, M; Kemel, Y; Stern, R; Phillips, A; Cholst, I; Kauff, N; Offit, K
MLA Citation
Hurley, K, Rubin, LR, Werner-Lin, A, Sagi, M, Kemel, Y, Stern, R, Phillips, A, Cholst, I, Kauff, N, and Offit, K. "Incorporating information regarding preimplantation genetic diagnosis into discussions concerning testing and risk management for BRCA1/2 mutations: a qualitative study of patient preferences." Cancer 118.24 (December 2012): 6270-6277.
PMID
22736296
Source
epmc
Published In
Cancer
Volume
118
Issue
24
Publish Date
2012
Start Page
6270
End Page
6277
DOI
10.1002/cncr.27695

Rare de novo germline copy-number variation in testicular cancer.

Although heritable factors are an important determinant of risk of early-onset cancer, the majority of these malignancies appear to occur sporadically without identifiable risk factors. Germline de novo copy-number variations (CNVs) have been observed in sporadic neurocognitive and cardiovascular disorders. We explored this mechanism in 382 genomes of 116 early-onset cancer case-parent trios and unaffected siblings. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were indeed found in 7% of 43 testicular germ cell tumor trios; this percentage exceeds background CNV rates and suggests a rare de novo genetic paradigm for susceptibility to some human malignancies.

Authors
Stadler, ZK; Esposito, D; Shah, S; Vijai, J; Yamrom, B; Levy, D; Lee, Y-H; Kendall, J; Leotta, A; Ronemus, M; Hansen, N; Sarrel, K; Rau-Murthy, R; Schrader, K; Kauff, N; Klein, RJ; Lipkin, SM; Murali, R; Robson, M; Sheinfeld, J; Feldman, D; Bosl, G; Norton, L; Wigler, M; Offit, K
MLA Citation
Stadler, ZK, Esposito, D, Shah, S, Vijai, J, Yamrom, B, Levy, D, Lee, Y-H, Kendall, J, Leotta, A, Ronemus, M, Hansen, N, Sarrel, K, Rau-Murthy, R, Schrader, K, Kauff, N, Klein, RJ, Lipkin, SM, Murali, R, Robson, M, Sheinfeld, J, Feldman, D, Bosl, G, Norton, L, Wigler, M, and Offit, K. "Rare de novo germline copy-number variation in testicular cancer." American Journal of Human Genetics 91.2 (August 2, 2012): 379-383.
PMID
22863192
Source
epmc
Published In
American Journal of Human Genetics
Volume
91
Issue
2
Publish Date
2012
Start Page
379
End Page
383
DOI
10.1016/j.ajhg.2012.06.019

Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer.

Multiple observational studies have suggested that breast cancer gene (BRCA)-associated ovarian cancers have improved survival compared with BRCA-negative ovarian cancers. However, most of those studies combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether BRCA1-associated and BRCA2-associated ovarian cancers were associated with different outcomes.This was a single-institution, retrospective analysis of patients who had a new diagnosis of histologically confirmed stage III or IV serous ovarian, fallopian tube, or primary peritoneal cancer between January 1, 1996 and February 1, 2011 and who underwent BRCA mutation testing on 1 of 2 institutional review board-approved follow-up studies. Patients who had been tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from including patients who were referred for genetic testing because of long survival.Data from 190 patients (143 BRCA-negative patients, 30 BRCA1-positive patients, and 17 BRCA2-positive patients) were analyzed. During the study period, 73 deaths were observed (60 BRCA-negative patients, 10 BRCA1-positive patients, 3 BRCA2-positive patients). The median follow-up for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90.7%, and 100% of BRCA-negative patients, BRCA1-positive patients, and BRCA2-positive patients were alive, respectively. On univariate analysis, age, BRCA2 mutations, debulking status, and type of first-line therapy (intravenous or intraperitoneal) were significant predictors of overall survival. On multivariate analysis, BRCA2 mutations (hazard ratio, 0.20; 95% confidence interval, 0.06-0.65; P = .007), but not BRCA1 mutations (hazard ratio, 0.70; 95% confidence interval, 0.36-1.38; P = .31), predicted for improved overall survival compared with BRCA-negative patients. When carriers of BRCA2 mutations were directly compared with carriers of BRCA1 mutations, BRCA2 mutations appeared to confer improved overall survival (hazard ratio, 0.29; 95% confidence interval, 0.08-1.05; P = .060), although this finding did not reach significance.The current data suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA-negative or having a BRCA1 mutation in high-grade serous ovarian cancer. This finding may have important implications for clinical trial design.

Authors
Hyman, DM; Zhou, Q; Iasonos, A; Grisham, RN; Arnold, AG; Phillips, MF; Bhatia, J; Levine, DA; Aghajanian, C; Offit, K; Barakat, RR; Spriggs, DR; Kauff, ND
MLA Citation
Hyman, DM, Zhou, Q, Iasonos, A, Grisham, RN, Arnold, AG, Phillips, MF, Bhatia, J, Levine, DA, Aghajanian, C, Offit, K, Barakat, RR, Spriggs, DR, and Kauff, ND. "Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer." Cancer 118.15 (August 2012): 3703-3709.
PMID
22139894
Source
epmc
Published In
Cancer
Volume
118
Issue
15
Publish Date
2012
Start Page
3703
End Page
3709
DOI
10.1002/cncr.26655

Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma.

BRCA-associated and sporadic ovarian cancers have different pathologic and clinical features. Our goal was to determine if BRCA mutation status is an independent predictor of residual tumor volume following primary surgical cytoreduction.We conducted a retrospective analysis of patients with FIGO stage IIIC-IV high-grade serous ovarian cancer classified for the presence or absence of germline BRCA mutations. The primary outcome was tumor-debulking status categorized as complete gross resection (0mm), optimal but visible disease (1-10 mm), or suboptimal debulking (>10 mm) following primary surgical cytoreduction. Overall survival by residual tumor size and BRCA status was also assessed as a secondary endpoint.Data from 367 patients (69 BRCA mutated, 298 BRCA wild-type) were analyzed. Rate of optimal tumor debulking (0-10 mm) in BRCA wild-type and BRCA-mutated patients were 70.1% and 84.1%, respectively (P=0.02). On univariate analysis, increasing age (10-year OR, 1.33; 95% CI, 1.07-1.65; P=0.01) and wild-type BRCA status (OR, 0.47; 95% CI, 0.23-0.94, P=0.03) were both significantly associated with suboptimal surgical outcome. On multivariate analysis, BRCA mutation status was no longer associated with residual tumor volume (OR, 0.63; 95% CI, 0.31-1.29; P=0.21) while age remained a borderline significant predictor (10-year OR, 1.25; 95% CI, 1.01-1.56; P=0.05). Both smaller residual tumor volume and mutant BRCA status were significantly associated with improved overall survival.BRCA mutation status is not associated with the rate of optimal tumor debulking at primary surgery after accounting for differences in patient age. Improved survival of BRCA carriers is unlikely the result of better surgical outcomes but instead intrinsic tumor biology.

Authors
Hyman, DM; Long, KC; Tanner, EJ; Grisham, RN; Arnold, AG; Bhatia, J; Phillips, MF; Spriggs, DR; Soslow, RA; Kauff, ND; Levine, DA
MLA Citation
Hyman, DM, Long, KC, Tanner, EJ, Grisham, RN, Arnold, AG, Bhatia, J, Phillips, MF, Spriggs, DR, Soslow, RA, Kauff, ND, and Levine, DA. "Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma." Gynecologic Oncology 126.2 (August 2012): 224-228.
PMID
22579790
Source
epmc
Published In
Gynecologic Oncology
Volume
126
Issue
2
Publish Date
2012
Start Page
224
End Page
228
DOI
10.1016/j.ygyno.2012.05.001

Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.

This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinoma-like morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012), more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n=4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% CI, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.

Authors
Soslow, RA; Han, G; Park, KJ; Garg, K; Olvera, N; Spriggs, DR; Kauff, ND; Levine, DA
MLA Citation
Soslow, RA, Han, G, Park, KJ, Garg, K, Olvera, N, Spriggs, DR, Kauff, ND, and Levine, DA. "Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma." Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc 25.4 (April 2012): 625-636.
PMID
22193042
Source
epmc
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
25
Issue
4
Publish Date
2012
Start Page
625
End Page
636
DOI
10.1038/modpathol.2011.183

Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers.We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer.Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43).These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.

Authors
Kotsopoulos, J; Lubinski, J; Salmena, L; Lynch, HT; Kim-Sing, C; Foulkes, WD; Ghadirian, P; Neuhausen, SL; Demsky, R; Tung, N; Ainsworth, P; Senter, L; Eisen, A; Eng, C; Singer, C; Ginsburg, O; Blum, J; Huzarski, T; Poll, A; Sun, P; Narod, SA; Hereditary Breast Cancer Clinical Study Group,
MLA Citation
Kotsopoulos, J, Lubinski, J, Salmena, L, Lynch, HT, Kim-Sing, C, Foulkes, WD, Ghadirian, P, Neuhausen, SL, Demsky, R, Tung, N, Ainsworth, P, Senter, L, Eisen, A, Eng, C, Singer, C, Ginsburg, O, Blum, J, Huzarski, T, Poll, A, Sun, P, Narod, SA, and Hereditary Breast Cancer Clinical Study Group, . "Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers." Breast Cancer Research : Bcr 14.2 (March 9, 2012): R42-null.
PMID
22405187
Source
epmc
Published In
Breast Cancer Research : Bcr
Volume
14
Issue
2
Publish Date
2012
Start Page
R42
DOI
10.1186/bcr3138

Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer.

Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown.A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed-to-expected (O:E) mutation prevalence was calculated for the entire group.Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first-, second-, or third-degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15).BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence.

Authors
Stadler, ZK; Salo-Mullen, E; Patil, SM; Pietanza, MC; Vijai, J; Saloustros, E; Hansen, NAL; Kauff, ND; Kurtz, RC; Kelsen, DP; Offit, K; Robson, ME
MLA Citation
Stadler, ZK, Salo-Mullen, E, Patil, SM, Pietanza, MC, Vijai, J, Saloustros, E, Hansen, NAL, Kauff, ND, Kurtz, RC, Kelsen, DP, Offit, K, and Robson, ME. "Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer." Cancer 118.2 (January 2012): 493-499.
PMID
21598239
Source
epmc
Published In
Cancer
Volume
118
Issue
2
Publish Date
2012
Start Page
493
End Page
499
DOI
10.1002/cncr.26191

Topotecan in patients with BRCA-associated and sporadic platinum-resistant ovarian, fallopian tube, and primary peritoneal cancers.

To evaluate the efficacy of topoisomerase I inhibitor, topotecan, in patients with recurrent BRCA+ versus BRCA- ovarian, fallopian tube, and primary peritoneal carcinomas.A single-institution retrospective analysis of platinum-resistant patients characterized for the presence or absence of known deleterious BRCA mutations. Patients received topotecan at a dose and schedule determined by their treating physician (five day or weekly). Response rate and progression-free survival (PFS) were assessed.A total of 50 patients (9 BRCA+, 41 BRCA-) were treated with topotecan. Both groups were well balanced in terms of age, stage, grade, and number of prior therapies. All patients had high-grade serous carcinoma. The clinical benefit rate in BRCA+ and BRCA- patients was 0% and 26.8% (6 PRs, 6 SDs), respectively (p=0.18). Median PFS in BRCA+ and BRCA- pts was 1.7 months (95% CI: 1.0-2.8 months) and 2.5 months (95%CI: 1.9-2.8 months), respectively (p=0.057). Median time to best response was 1.9 months, and median response duration 2.6 months.This analysis in a heavily pretreated cohort of patients fails to support the superiority of topotecan in BRCA+ platinum-resistant ovarian, fallopian tube, and primary peritoneal cancers. Further study of this class of agents, specifically in less heavily-pretreated patients, may still be warranted.

Authors
Hyman, DM; Zhou, Q; Arnold, AG; Grisham, RN; Iasonos, A; Kauff, ND; Spriggs, D
MLA Citation
Hyman, DM, Zhou, Q, Arnold, AG, Grisham, RN, Iasonos, A, Kauff, ND, and Spriggs, D. "Topotecan in patients with BRCA-associated and sporadic platinum-resistant ovarian, fallopian tube, and primary peritoneal cancers." Gynecologic Oncology 123.2 (November 2011): 196-199.
PMID
21855118
Source
epmc
Published In
Gynecologic Oncology
Volume
123
Issue
2
Publish Date
2011
Start Page
196
End Page
199
DOI
10.1016/j.ygyno.2011.07.019

Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40years of age and younger.

The hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to examine risk factors and outcomes in patients 40 years of age and younger with endometrial cancer.We performed a retrospective cohort study of patients aged 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry was performed. Cases were analyzed according to the presence of DNA MMR protein defects. Standard two-sided statistical tests were performed.Of the 56 identified patients, the median age was 36 years (range, 24-40). The majority of the endometrial carcinomas were of endometrioid histology (91%), stage I (71%), and FIGO grade 1 (59%). Abnormal DNA MMR was found in 9 cases (16%). Cases with abnormal DNA MMR had lower body mass index (BMI) (P=0.05), and had a family history suggestive of Lynch syndrome (P=0.001). Tumors were more likely to have advanced stage disease (P<0.001), be high grade (P<0.001), have deep myometrial invasion (P<0.001), and have lymphovascular invasion (P=0.002). Cases with abnormal DNA MMR had significantly worse overall survival (P=0.028) and progression-free survival (P=0.042).Endometrial cancer is rare in women aged 40 years or less. In this group of patients, loss of DNA MMR was associated with lower BMI, worse clinicopathologic factors, and worse outcome. These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis.

Authors
Shih, KK; Garg, K; Levine, DA; Kauff, ND; Abu-Rustum, NR; Soslow, RA; Barakat, RR
MLA Citation
Shih, KK, Garg, K, Levine, DA, Kauff, ND, Abu-Rustum, NR, Soslow, RA, and Barakat, RR. "Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40years of age and younger." Gynecologic Oncology 123.1 (October 2011): 88-94.
PMID
21742371
Source
epmc
Published In
Gynecologic Oncology
Volume
123
Issue
1
Publish Date
2011
Start Page
88
End Page
94
DOI
10.1016/j.ygyno.2011.06.005

Hereditary ovarian cancer: recent molecular insights and their impact on screening strategies.

PURPOSE OF REVIEW: This review will focus on the implications of BRCA status in the patient with high-grade serous ovarian cancer, the differences between BRCA1 and BRCA2 mutations, and the most effective risk-reducing strategies. RECENT FINDINGS: Women with BRCA-associated epithelial ovarian cancer represent a unique group who commonly are diagnosed at a younger age, have advanced high-grade serous disease, have improved sensitivity to platinum-based chemotherapy in both the upfront and recurrent setting, and have an overall improved prognosis. Promising novel therapeutic agents such as poly (ADP-ribose) polymerase inhibitors have increased activity in patients with inherited BRCA mutations and may also have a role in patients with noninherited tumors that have decreased BRCA activity. Risk-reducing salpingo-oophorectomy (RRSO) is effective in decreasing risks of both breast and gynecologic cancer in women with BRCA mutations. However, when counseling women at inherited risk, the inherent phenotypical differences between BRCA1 and BRCA2 mutations must be considered. SUMMARY: Patients with BRCA-associated epithelial ovarian cancer have improved response to platinum-based chemotherapy, improved survival, and may be appropriate candidates for treatment with novel targeted therapies. RRSO remains the most effective risk-reduction strategy in women with BRCA mutations.

Authors
Long, KC; Kauff, ND
MLA Citation
Long, KC, and Kauff, ND. "Hereditary ovarian cancer: recent molecular insights and their impact on screening strategies." Current Opinion in Oncology 23.5 (September 2011): 526-530. (Review)
PMID
21734577
Source
epmc
Published In
Current Opinion in Oncology
Volume
23
Issue
5
Publish Date
2011
Start Page
526
End Page
530
DOI
10.1097/cco.0b013e3283499da9

Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status.

Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women).

Authors
Skates, SJ; Mai, P; Horick, NK; Piedmonte, M; Drescher, CW; Isaacs, C; Armstrong, DK; Buys, SS; Rodriguez, GC; Horowitz, IR; Berchuck, A; Daly, MB; Domchek, S; Cohn, DE; Van Le, L; Schorge, JO; Newland, W; Davidson, SA; Barnes, M; Brewster, W; Azodi, M; Nerenstone, S; Kauff, ND; Fabian, CJ; Sluss, PM; Nayfield, SG; Kasten, CH; Finkelstein, DM; Greene, MH; Lu, K
MLA Citation
Skates, SJ, Mai, P, Horick, NK, Piedmonte, M, Drescher, CW, Isaacs, C, Armstrong, DK, Buys, SS, Rodriguez, GC, Horowitz, IR, Berchuck, A, Daly, MB, Domchek, S, Cohn, DE, Van Le, L, Schorge, JO, Newland, W, Davidson, SA, Barnes, M, Brewster, W, Azodi, M, Nerenstone, S, Kauff, ND, Fabian, CJ, Sluss, PM, Nayfield, SG, Kasten, CH, Finkelstein, DM, Greene, MH, and Lu, K. "Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status." Cancer Prevention Research (Philadelphia, Pa.) 4.9 (September 2011): 1401-1408.
PMID
21893500
Source
epmc
Published In
Cancer Prevention Research
Volume
4
Issue
9
Publish Date
2011
Start Page
1401
End Page
1408
DOI
10.1158/1940-6207.capr-10-0402

Assessment of the prevalence of de novo mutations in the BRCA1 and BRCA2 genes.

Authors
Zhang, L; Fleischut, MH; Kohut, K; Spencer, S; Wong, K; Stadler, ZK; Kauff, ND; Offit, K; Robson, ME
MLA Citation
Zhang, L, Fleischut, MH, Kohut, K, Spencer, S, Wong, K, Stadler, ZK, Kauff, ND, Offit, K, and Robson, ME. "Assessment of the prevalence of de novo mutations in the BRCA1 and BRCA2 genes." Clinical Genetics 80.1 (July 2011): 97-98. (Letter)
PMID
21649643
Source
epmc
Published In
Clinical Genetics
Volume
80
Issue
1
Publish Date
2011
Start Page
97
End Page
98
DOI
10.1111/j.1399-0004.2011.01691.x

Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women.

Several single nucleotide polymorphisms (SNPs) are associated with an increased risk of breast cancer. The clinical utility of genotyping individuals at these loci is not known. Subjects were 519 unaffected women without BRCA mutations. Gail, Claus, and IBIS models were used to estimate absolute breast cancer risks. Subjects were then genotyped at 15 independent risk loci. Published per-allele and genotype-specific odds ratios were used to calculate the composite cumulative genomic risk (CGR) for each subject. Affected age- and ethnicity-matched BRCA mutation-negative women were also genotyped as a comparison group for the calculation of discriminatory accuracy. The CGR was used to adjust absolute breast cancer risks calculated by Gail, Claus and IBIS models to determine the proportion of subjects whose recommendations for chemoprevention or MRI screening might be altered (reclassified) by such adjustment. Mean lifetime breast cancer risks calculated using the Gail, Claus, and IBIS models were 19.4, 13.0, and 17.7%, respectively. CGR did not correlate with breast cancer risk as calculated using any model. CGR was significantly higher in affected women (mean 3.35 vs. 3.12, P = 0.009). The discriminatory accuracy of the CGR alone was 0.55 (SE 0.019; P = 0.006). CGR adjustment of model-derived absolute risk estimates would have altered clinical recommendations for chemoprevention in 11-19% of subjects and for MRI screening in 8-32%. CGR has limited discriminatory accuracy. However, the use of a genomic risk term to adjust model-derived estimates has the potential to alter individual recommendations. These observations warrant investigation to evaluate the calibration of adjusted risk estimates.

Authors
Comen, E; Balistreri, L; Gönen, M; Dutra-Clarke, A; Fazio, M; Vijai, J; Stadler, Z; Kauff, N; Kirchhoff, T; Hudis, C; Offit, K; Robson, M
MLA Citation
Comen, E, Balistreri, L, Gönen, M, Dutra-Clarke, A, Fazio, M, Vijai, J, Stadler, Z, Kauff, N, Kirchhoff, T, Hudis, C, Offit, K, and Robson, M. "Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women." Breast Cancer Research and Treatment 127.2 (June 2011): 479-487.
PMID
20957429
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
127
Issue
2
Publish Date
2011
Start Page
479
End Page
487
DOI
10.1007/s10549-010-1215-2

The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing.

An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association.Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data.No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52).These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.

Authors
Pharoah, PDP; Palmieri, RT; Ramus, SJ; Gayther, SA; Andrulis, IL; Anton-Culver, H; Antonenkova, N; Antoniou, AC; Goldgar, D; BCFR Investigators, ; Beattie, MS; Beckmann, MW; Birrer, MJ; Bogdanova, N; Bolton, KL; Brewster, W; Brooks-Wilson, A; Brown, R; Butzow, R; Caldes, T; Caligo, MA; Campbell, I; Chang-Claude, J; Chen, YA; Cook, LS; Couch, FJ; Cramer, DW; Cunningham, JM; Despierre, E; Doherty, JA; Dörk, T; Dürst, M; Eccles, DM; Ekici, AB; Easton, D; EMBRACE Investigators, ; Fasching, PA; de Fazio, A; Fenstermacher, DA; Flanagan, JM; Fridley, BL; Friedman, E; Gao, B; Sinilnikova, O; GEMO Study Collaborators, ; Gentry-Maharaj, A; Godwin, AK; Goode, EL; Goodman, MT; Gross, J; Hansen, TVO; Harnett, P; Rookus, M; HEBON Investigators, ; Heikkinen, T; Hein, R; Høgdall, C; Høgdall, E; Iversen, ES; Jakubowska, A; Johnatty, SE; Karlan, BY; Kauff, ND; Kaye, SB; Chenevix-Trench, G; kConFab Investigators and the Consortium of Investigators of Modifiers of BRCA1/2, ; Kelemen, LE; Kiemeney, LA; Kjaer, SK; Lambrechts, D; Lapolla, JP; Lázaro, C; Le, ND; Leminen, A; Leunen, K; Levine, DA; Lu, Y; Lundvall, L; Macgregor, S; Marees, T; Massuger, LF; McLaughlin, JR; Menon, U; Montagna, M; Moysich, KB; Narod, SA; Nathanson, KL; Nedergaard, L; Ness, RB; Nevanlinna, H; Nickels, S; Osorio, A; Paul, J; Pearce, CL; Phelan, CM; Pike, MC; Radice, P; Rossing, MA; Schildkraut, JM; Sellers, TA; Singer, CF; Song, H; Stram, DO; Sutphen, R; Lindblom, A; SWE-BRCA Investigators, ; Terry, KL; Tsai, Y-Y; van Altena, AM; Vergote, I; Vierkant, RA; Vitonis, AF; Walsh, C; Wang-Gohrke, S; Wappenschmidt, B; Wu, AH; Ziogas, A; Berchuck, A; Risch, HA; Ovarian Cancer Association Consortium,
MLA Citation
Pharoah, PDP, Palmieri, RT, Ramus, SJ, Gayther, SA, Andrulis, IL, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Goldgar, D, BCFR Investigators, , Beattie, MS, Beckmann, MW, Birrer, MJ, Bogdanova, N, Bolton, KL, Brewster, W, Brooks-Wilson, A, Brown, R, Butzow, R, Caldes, T, Caligo, MA, Campbell, I, Chang-Claude, J, Chen, YA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Despierre, E, Doherty, JA, Dörk, T, Dürst, M, Eccles, DM, Ekici, AB, Easton, D, EMBRACE Investigators, , Fasching, PA, de Fazio, A, Fenstermacher, DA, Flanagan, JM, Fridley, BL, Friedman, E, Gao, B, Sinilnikova, O, GEMO Study Collaborators, , Gentry-Maharaj, A, Godwin, AK, Goode, EL, Goodman, MT, Gross, J, Hansen, TVO, Harnett, P, Rookus, M, HEBON Investigators, , Heikkinen, T, Hein, R, Høgdall, C, Høgdall, E, Iversen, ES, Jakubowska, A, Johnatty, SE, Karlan, BY, Kauff, ND, Kaye, SB, Chenevix-Trench, G, kConFab Investigators and the Consortium of Investigators of Modifiers of BRCA1/2, , Kelemen, LE, Kiemeney, LA, Kjaer, SK, Lambrechts, D, Lapolla, JP, Lázaro, C, Le, ND, Leminen, A, Leunen, K, Levine, DA, Lu, Y, Lundvall, L, Macgregor, S, Marees, T, Massuger, LF, McLaughlin, JR, Menon, U, Montagna, M, Moysich, KB, Narod, SA, Nathanson, KL, Nedergaard, L, Ness, RB, Nevanlinna, H, Nickels, S, Osorio, A, Paul, J, Pearce, CL, Phelan, CM, Pike, MC, Radice, P, Rossing, MA, Schildkraut, JM, Sellers, TA, Singer, CF, Song, H, Stram, DO, Sutphen, R, Lindblom, A, SWE-BRCA Investigators, , Terry, KL, Tsai, Y-Y, van Altena, AM, Vergote, I, Vierkant, RA, Vitonis, AF, Walsh, C, Wang-Gohrke, S, Wappenschmidt, B, Wu, AH, Ziogas, A, Berchuck, A, Risch, HA, and Ovarian Cancer Association Consortium, . "The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 17.11 (June 2011): 3742-3750.
PMID
21385923
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
17
Issue
11
Publish Date
2011
Start Page
3742
End Page
3750
DOI
10.1158/1078-0432.ccr-10-3405

Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity.

Patients with BRCA-associated ovarian cancer (OC) have a survival advantage over those with sporadic OC. To further explore this, we examined the impact of prognostic factors on disease-free survival (DFS) and overall survival (OS) in patients with known BRCA mutation status.We reviewed stage III-IV OC patients treated at our institution between 1 December 1996 and 30 September 2006 and also tested on protocol for BRCA mutations. Impact on DFS and OS was determined by Kaplan-Meier analysis and a Cox proportional hazards model.Of the 110 patients, 36 had deleterious BRCA mutations [BRCA (+)] and 74 were BRCA wild type [BRCA(-)]. Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients were platinum sensitive (P = 0.60). Median OS was longer for BRCA (+) patients (not reached versus 67.8 months; P = 0.02), but DFS was similar (26.9 versus 24.0, P = 0.3). On multivariate analysis, OS correlated with primary platinum sensitivity [HR = 0.15; 95% CI (confidence interval) 0.06-0.34] and BRCA (+) mutation status (HR = 0.33; 95% CI 0.12-0.86).BRCA mutation status predicted OS independent of primary platinum sensitivity, suggesting that underlying tumor biology contributes to disease outcome and may be worthy of consideration in future clinical trial design.

Authors
Gallagher, DJ; Konner, JA; Bell-McGuinn, KM; Bhatia, J; Sabbatini, P; Aghajanian, CA; Offit, K; Barakat, RR; Spriggs, DR; Kauff, ND
MLA Citation
Gallagher, DJ, Konner, JA, Bell-McGuinn, KM, Bhatia, J, Sabbatini, P, Aghajanian, CA, Offit, K, Barakat, RR, Spriggs, DR, and Kauff, ND. "Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity." Annals of Oncology : Official Journal of the European Society for Medical Oncology 22.5 (May 2011): 1127-1132.
PMID
21084428
Source
epmc
Published In
Annals of Oncology
Volume
22
Issue
5
Publish Date
2011
Start Page
1127
End Page
1132
DOI
10.1093/annonc/mdq577

Genetic counseling's critical role in managing hereditary cancers

Authors
Kauff, ND
MLA Citation
Kauff, ND. "Genetic counseling's critical role in managing hereditary cancers." Contemporary Ob/Gyn 56.4 (April 1, 2011): 34-null.
Source
scopus
Published In
Contemporary Ob/Gyn
Volume
56
Issue
4
Publish Date
2011
Start Page
34

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Authors
Mulligan, AM; Couch, FJ; Barrowdale, D; Domchek, SM; Eccles, D; Nevanlinna, H; Ramus, SJ; Robson, M; Sherman, M; Spurdle, AB; Wappenschmidt, B; Lee, A; McGuffog, L; Healey, S; Sinilnikova, OM; Janavicius, R; Hansen, TV; Nielsen, FC; Ejlertsen, B; Osorio, A; Muñoz-Repeto, I; Durán, M; Godino, J; Pertesi, M; Benítez, J; Peterlongo, P; Manoukian, S; Peissel, B; Zaffaroni, D; Cattaneo, E; Bonanni, B; Viel, A; Pasini, B; Papi, L; Ottini, L; Savarese, A; Bernard, L; Radice, P; Hamann, U; Verheus, M; Meijers-Heijboer, HEJ; Wijnen, J; Gómez García, EB; Nelen, MR; Kets, CM; Seynaeve, C; Tilanus-Linthorst, MMA; van der Luijt, RB; van Os, T; Rookus, M; Frost, D; Jones, JL; Evans, DG; Lalloo, F; Eeles, R; Izatt, L; Adlard, J; Davidson, R; Cook, J; Donaldson, A; Dorkins, H; Gregory, H; Eason, J; Houghton, C; Barwell, J; Side, LE; McCann, E; Murray, A; Peock, S; Godwin, AK; Schmutzler, RK; Rhiem, K; Engel, C; Meindl, A; Ruehl, I; Arnold, N; Niederacher, D; Sutter, C; Deissler, H; Gadzicki, D; Kast, K; Preisler-Adams, S; Varon-Mateeva, R; Schoenbuchner, I; Fiebig, B; Heinritz, W; Schäfer, D; Gevensleben, H; Caux-Moncoutier, V; Fassy-Colcombet, M; Cornelis, F; Mazoyer, S; Léoné, M; Boutry-Kryza, N; Hardouin, A; Berthet, P; Muller, D; Fricker, J-P; Mortemousque, I; Pujol, P; Coupier, I; Lebrun, M; Kientz, C; Longy, M; Sevenet, N; Stoppa-Lyonnet, D; Isaacs, C; Caldes, T; de la Hoya, M; Heikkinen, T; Aittomäki, K; Blanco, I; Lazaro, C; Barkardottir, RB; Soucy, P; Dumont, M; Simard, J; Montagna, M; Tognazzo, S; D'Andrea, E; Fox, S; Yan, M; Rebbeck, T; Olopade, O; Weitzel, JN; Lynch, HT; Ganz, PA; Tomlinson, GE; Wang, X; Fredericksen, Z; Pankratz, VS; Lindor, NM; Szabo, C; Offit, K; Sakr, R; Gaudet, M; Bhatia, J; Kauff, N; Singer, CF; Tea, M-K; Gschwantler-Kaulich, D; Fink-Retter, A; Mai, PL; Greene, MH; Imyanitov, E; O'Malley, FP; Ozcelik, H; Glendon, G; Toland, AE; Gerdes, A-M; Thomassen, M; Kruse, TA; Jensen, UB; Skytte, A-B; Caligo, MA; Soller, M; Henriksson, K; Wachenfeldt, VA; Arver, B; Stenmark-Askmalm, M; Karlsson, P; Ding, YC; Neuhausen, SL; Beattie, M; Pharoah, PDP; Moysich, KB; Nathanson, KL; Karlan, BY; Gross, J; John, EM; Daly, MB; Buys, SM; Southey, MC; Hopper, JL; Terry, MB; Chung, W; Miron, AF; Goldgar, D; Chenevix-Trench, G; Easton, DF; Andrulis, IL; Antoniou, AC; Breast Cancer Family Registry, ; EMBRACE, ; GEMO Study Collaborators, ; HEBON, ; kConFab Investigators, ; Ontario Cancer Genetics Network, ; SWE-BRCA, ; CIMBA,
MLA Citation
Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TV, Nielsen, FC, Ejlertsen, B, Osorio, A, Muñoz-Repeto, I, Durán, M, Godino, J, Pertesi, M, Benítez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Gómez García, EB, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, van Os, T, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schäfer, D, Gevensleben, H, Caux-Moncoutier, V, Fassy-Colcombet, M, Cornelis, F, Mazoyer, S, Léoné, M, Boutry-Kryza, N, Hardouin, A, Berthet, P, Muller, D, Fricker, J-P, Mortemousque, I, Pujol, P, Coupier, I, Lebrun, M, Kientz, C, Longy, M, Sevenet, N, Stoppa-Lyonnet, D, Isaacs, C, Caldes, T, de la Hoya, M, Heikkinen, T, Aittomäki, K, Blanco, I, Lazaro, C, Barkardottir, RB, Soucy, P, Dumont, M, Simard, J, Montagna, M, Tognazzo, S, D'Andrea, E, Fox, S, Yan, M, Rebbeck, T, Olopade, O, Weitzel, JN, Lynch, HT, Ganz, PA, Tomlinson, GE, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Szabo, C, Offit, K, Sakr, R, Gaudet, M, Bhatia, J, Kauff, N, Singer, CF, Tea, M-K, Gschwantler-Kaulich, D, Fink-Retter, A, Mai, PL, Greene, MH, Imyanitov, E, O'Malley, FP, Ozcelik, H, Glendon, G, Toland, AE, Gerdes, A-M, Thomassen, M, Kruse, TA, Jensen, UB, Skytte, A-B, Caligo, MA, Soller, M, Henriksson, K, Wachenfeldt, VA, Arver, B, Stenmark-Askmalm, M, Karlsson, P, Ding, YC, Neuhausen, SL, Beattie, M, Pharoah, PDP, Moysich, KB, Nathanson, KL, Karlan, BY, Gross, J, John, EM, Daly, MB, Buys, SM, Southey, MC, Hopper, JL, Terry, MB, Chung, W, Miron, AF, Goldgar, D, Chenevix-Trench, G, Easton, DF, Andrulis, IL, Antoniou, AC, Breast Cancer Family Registry, , EMBRACE, , GEMO Study Collaborators, , HEBON, , kConFab Investigators, , Ontario Cancer Genetics Network, , SWE-BRCA, , and CIMBA, . "Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2." Breast Cancer Research : Bcr 13.6 (January 2011): R110-null.
PMID
22053997
Source
epmc
Published In
Breast Cancer Research : Bcr
Volume
13
Issue
6
Publish Date
2011
Start Page
R110
DOI
10.1186/bcr3052

Genome-wide association studies of cancer predisposition.

Genome-wide association studies (GWAS) have now been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer. For most discovered germline risk variants, the per allele effect size is small (<1.5) and the biologic mechanism of the detected association remains unexplained. Exceptions are the risk variants identified in JAK2 in myeloproliferative neoplasm and in the KITLG gene in testicular cancer, which are each associated with nearly a 3-fold increased risk of disease. GWAS have provided an efficient approach to identifying common, low-penetrance risk variants, and have implicated several novel cancer susceptibility loci. However, the identified low-penetrance risk variants explain only a small fraction of the heritability of cancer and the clinical usefulness of using these variants for cancer-risk prediction is to date limited. Studies involving more heterogeneous populations, determination of the causal variants, and functional studies are now necessary to further elucidate the potential biologic and clinical significance of the observed associations.

Authors
Stadler, ZK; Vijai, J; Thom, P; Kirchhoff, T; Hansen, NAL; Kauff, ND; Robson, M; Offit, K
MLA Citation
Stadler, ZK, Vijai, J, Thom, P, Kirchhoff, T, Hansen, NAL, Kauff, ND, Robson, M, and Offit, K. "Genome-wide association studies of cancer predisposition." Hematology/Oncology Clinics of North America 24.5 (October 2010): 973-996. (Review)
PMID
20816582
Source
epmc
Published In
Hematology/Oncology Clinics of North America
Volume
24
Issue
5
Publish Date
2010
Start Page
973
End Page
996
DOI
10.1016/j.hoc.2010.06.009

SGO White Paper on ovarian cancer: etiology, screening and surveillance.

Ovarian cancer is a heterogeneous, rapidly progressive, highly lethal disease of low prevalence. The etiology remains poorly understood. Numerous risk factors have been identified, the most prominent involving an inherited predisposition in 10% of cases. Women with germline mutations associated with Hereditary Breast/Ovarian Cancer and Lynch syndromes have dramatically elevated risks (up to 46% and 12%, respectively). Risk-reducing salpingo-oophorectomy is the best method to prevent ovarian cancer in these high-risk women. Significant risk reduction is also seen in the general population who use oral contraceptives. Since up to 89% patients with early-stage disease have symptoms prior to diagnosis, increased awareness of the medical community may facilitate further workup in patients who otherwise would have had a delay. Despite enormous effort, there is no proof that routine screening for ovarian cancer in either the high-risk or general populations with serum markers, sonograms, or pelvic examinations decreases mortality. Further evaluation is needed to determine whether any novel biomarkers, or panels of markers, have clinical utility in early detection. Prospective clinical trials have to be designed and completed prior to offering of any of these new diagnostic tests. CA125 is currently the only biomarker recommended for monitoring of therapy as well as detection of recurrence. This commentary provides an overview on the background, screening and surveillance of ovarian cancer.

Authors
Schorge, JO; Modesitt, SC; Coleman, RL; Cohn, DE; Kauff, ND; Duska, LR; Herzog, TJ
MLA Citation
Schorge, JO, Modesitt, SC, Coleman, RL, Cohn, DE, Kauff, ND, Duska, LR, and Herzog, TJ. "SGO White Paper on ovarian cancer: etiology, screening and surveillance." Gynecologic Oncology 119.1 (October 2010): 7-17. (Review)
PMID
20692025
Source
epmc
Published In
Gynecologic Oncology
Volume
119
Issue
1
Publish Date
2010
Start Page
7
End Page
17
DOI
10.1016/j.ygyno.2010.06.003

Genome-wide association studies of cancer.

Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited.

Authors
Stadler, ZK; Thom, P; Robson, ME; Weitzel, JN; Kauff, ND; Hurley, KE; Devlin, V; Gold, B; Klein, RJ; Offit, K
MLA Citation
Stadler, ZK, Thom, P, Robson, ME, Weitzel, JN, Kauff, ND, Hurley, KE, Devlin, V, Gold, B, Klein, RJ, and Offit, K. "Genome-wide association studies of cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 28.27 (September 2010): 4255-4267.
PMID
20585100
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
27
Publish Date
2010
Start Page
4255
End Page
4267
DOI
10.1200/jco.2009.25.7816

Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families.

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.

Authors
Stadler, ZK; Saloustros, E; Hansen, NAL; Schluger, AE; Kauff, ND; Offit, K; Robson, ME
MLA Citation
Stadler, ZK, Saloustros, E, Hansen, NAL, Schluger, AE, Kauff, ND, Offit, K, and Robson, ME. "Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families." Breast Cancer Research and Treatment 123.2 (September 2010): 581-585.
PMID
20221693
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
123
Issue
2
Publish Date
2010
Start Page
581
End Page
585
DOI
10.1007/s10549-010-0818-y

Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2.

Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations (true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean follow up of 4.9 years (total of 1,962 person years).Four invasive BC were expected, whereas two were observed, for an age-adjusted SIR of 0.52 (95% CI 0.13-2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57-9.19).There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population based guidelines for breast cancer screening.

Authors
Domchek, SM; Gaudet, MM; Stopfer, JE; Fleischaut, MH; Powers, J; Kauff, N; Offit, K; Nathanson, KL; Robson, M
MLA Citation
Domchek, SM, Gaudet, MM, Stopfer, JE, Fleischaut, MH, Powers, J, Kauff, N, Offit, K, Nathanson, KL, and Robson, M. "Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2." Breast Cancer Research and Treatment 119.2 (January 2010): 409-414.
PMID
19885732
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
119
Issue
2
Publish Date
2010
Start Page
409
End Page
414
DOI
10.1007/s10549-009-0611-y

Weighing options for cancer risk reduction in carriers of BRCA1 and BRCA2 mutations.

Authors
Stadler, ZK; Kauff, ND
MLA Citation
Stadler, ZK, and Kauff, ND. "Weighing options for cancer risk reduction in carriers of BRCA1 and BRCA2 mutations." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 28.2 (January 2010): 189-191.
PMID
19996025
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
2
Publish Date
2010
Start Page
189
End Page
191
DOI
10.1200/jco.2009.25.6875

A review of the challenges faced in the conservative treatment of young women with endometrial carcinoma and risk of ovarian cancer.

OBJECTIVE: The standard management for women diagnosed with endometrial carcinoma (EC) is hysterectomy with salpingo-oophorectomy. However, more conservative treatment approaches, including uterine and ovarian preservation, may be used for women who have a strong desire to maintain fertility in spite of potential oncologic risks. METHODS: We reviewed the literature regarding fertility-preserving treatment for EC. We also conducted medical chart reviews for two young patients diagnosed with EC whose treatment deviated from the standard approach in order to preserve fertility. These patients were subsequently diagnosed with ovarian cancer. Our review summarizes the literature regarding the clinical and emotional implications of fertility preservation in young women. CASES: Two young nulliparous women (29 and 23 years, respectively) with grade 1 endometrioid adenocarcinoma were initially treated with conservative fertility-sparing endocrine therapy. Upon failure of endocrine treatment both women underwent hysterectomy and staging with ovarian preservation. During surveillance, both women were subsequently diagnosed with ovarian carcinoma and underwent bilateral salpingo-oophorectomy (BSO) and comprehensive staging. CONCLUSION: The management of young women with endometrial cancer can be complex and challenging. Patients and physicians are confronted with the dilemma of following standard surgical guidelines versus the desire to maintain fertility and avoid surgical menopause. Careful oncologic, psychotherapeutic, genetic and reproductive counseling is advised before offering a non-standard treatment strategy to young endometrial cancer patients.

Authors
Zivanovic, O; Carter, J; Kauff, ND; Barakat, RR
MLA Citation
Zivanovic, O, Carter, J, Kauff, ND, and Barakat, RR. "A review of the challenges faced in the conservative treatment of young women with endometrial carcinoma and risk of ovarian cancer." Gynecologic Oncology 115.3 (December 2009): 504-509. (Review)
PMID
19758691
Source
epmc
Published In
Gynecologic Oncology
Volume
115
Issue
3
Publish Date
2009
Start Page
504
End Page
509
DOI
10.1016/j.ygyno.2009.08.011

Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers.

BRCA1 mutation carriers have a high rate of both breast and ovarian cancer. Tamoxifen is a selective estrogen receptor modulator (SERM), which is used for the treatment of primary breast cancer and for the prevention of contralateral breast cancer. Our objective is to assess if tamoxifen treatment is associated with an increase in the subsequent risk of ovarian cancer among women with a BRCA1 mutation.A matched case-control study was performed. Cases were 154 women with ovarian cancer and a previous history of breast cancer. Controls were 560 women with no ovarian cancer and a history of breast cancer. All cases and controls carry a deleterious BRCA1 mutation. Cases and controls were matched for year of birth, age at diagnosis of breast cancer and country of residence. The effect of tamoxifen treatment on the risk of subsequent ovarian cancer was estimated using conditional logistic regression.The unadjusted odds ratio for ovarian cancer, given previous tamoxifen treatment was 0.89 (95% CI 0.54-1.49, p=0.66). After adjusting for other treatments, the odds ratio was 0.78 (95% CI 0.46-1.33, p=0.36).Tamoxifen treatment for breast cancer does not appear to increase the risk of ovarian cancer in BRCA1 mutation carriers.

Authors
Vicus, D; Rosen, B; Lubinski, J; Domchek, S; Kauff, ND; Lynch, HT; Isaacs, C; Tung, N; Sun, P; Narod, SA; Hereditary Ovarian Cancer Clinical Study Group,
MLA Citation
Vicus, D, Rosen, B, Lubinski, J, Domchek, S, Kauff, ND, Lynch, HT, Isaacs, C, Tung, N, Sun, P, Narod, SA, and Hereditary Ovarian Cancer Clinical Study Group, . "Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers." Gynecologic Oncology 115.1 (October 2009): 135-137.
PMID
19577280
Source
epmc
Published In
Gynecologic Oncology
Volume
115
Issue
1
Publish Date
2009
Start Page
135
End Page
137
DOI
10.1016/j.ygyno.2009.06.012

ATR mutations in endometrial cancer: a window into the role of mismatch repair defects.

Authors
Kauff, ND
MLA Citation
Kauff, ND. "ATR mutations in endometrial cancer: a window into the role of mismatch repair defects." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 27.19 (July 2009): 3077-3078. (Review)
PMID
19470916
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
19
Publish Date
2009
Start Page
3077
End Page
3078
DOI
10.1200/jco.2009.22.2125

Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities.

Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a high risk for endometrial cancer (EC) and frequently present with a gynecologic cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumors. The revised Bethesda Guidelines provide screening criteria for HNPCC in colorectal cancers. However, there are currently no such screening recommendations for women with endometrial carcinoma. We applied some of the colorectal cancer screening criteria, including age and tumor morphology, to endometrial endometrioid carcinoma. The purpose of this study was to describe patient and tumor characteristics and to assess the ability of these criteria to enhance detection of mismatch repair (MMR) deficiency, and hence HNPCC in EC. Immunohistochemistry (IHC) for DNA mismatch repair (IHC-MMR) proteins was performed in a defined subset of patients with EC. This included women younger than 50 years of age and women >or=50 years whose tumors showed morphologic features suggestive of MMR deficiency (TM-MMR). The extent of IHC-MMR in the older patient group was compared with that in a comparison group of EC >or=50 years that was previously analyzed for microsatellite instability status. Seventy-one patients met the selection criteria for IHC testing; 32 (45%) showed abnormal results. The rate of IHC abnormality in the younger group was approximately 30% with a nearly equal distribution of MLH1/PMS2 and MSH2/MSH6 abnormalities. In the older age group, TM-MMR triggered IHC analysis in 31 of 34 cases. Of these, 18 cases showed loss of IHC-MMR (58% of cases), 7 with loss of MSH2/MSH6. In contrast, the rate of microsatellite instability in the comparison group was only 21%. The IHC abnormal group showed more frequent tumor infiltrating lymphocytes, dedifferentiated EC, more tumors centered in the lower uterine segment, and more frequent synchronous clear cell carcinomas of the ovary than tumors with a normal immunophenotype. Although many of the patients with loss of IHC-MMR showed personal and/or family history (13 of 32) of HNPCC-associated tumors, most did not. Tumor morphology (TM-MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC.

Authors
Garg, K; Leitao, MM; Kauff, ND; Hansen, J; Kosarin, K; Shia, J; Soslow, RA
MLA Citation
Garg, K, Leitao, MM, Kauff, ND, Hansen, J, Kosarin, K, Shia, J, and Soslow, RA. "Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities." The American Journal of Surgical Pathology 33.6 (June 2009): 925-933.
PMID
19238076
Source
epmc
Published In
The American Journal of Surgical Pathology
Volume
33
Issue
6
Publish Date
2009
Start Page
925
End Page
933
DOI
10.1097/pas.0b013e318197a046

Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.

Risk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not.All reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis.Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers.The summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

Authors
Rebbeck, TR; Kauff, ND; Domchek, SM
MLA Citation
Rebbeck, TR, Kauff, ND, and Domchek, SM. "Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers." Journal of the National Cancer Institute 101.2 (January 13, 2009): 80-87.
PMID
19141781
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
101
Issue
2
Publish Date
2009
Start Page
80
End Page
87
DOI
10.1093/jnci/djn442

Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.

Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model.During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance.The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.

Authors
Kauff, ND; Domchek, SM; Friebel, TM; Robson, ME; Lee, J; Garber, JE; Isaacs, C; Evans, DG; Lynch, H; Eeles, RA; Neuhausen, SL; Daly, MB; Matloff, E; Blum, JL; Sabbatini, P; Barakat, RR; Hudis, C; Norton, L; Offit, K; Rebbeck, TR
MLA Citation
Kauff, ND, Domchek, SM, Friebel, TM, Robson, ME, Lee, J, Garber, JE, Isaacs, C, Evans, DG, Lynch, H, Eeles, RA, Neuhausen, SL, Daly, MB, Matloff, E, Blum, JL, Sabbatini, P, Barakat, RR, Hudis, C, Norton, L, Offit, K, and Rebbeck, TR. "Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.8 (March 2008): 1331-1337.
PMID
18268356
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
8
Publish Date
2008
Start Page
1331
End Page
1337
DOI
10.1200/JCO.2007.13.9626

Is It time to stratify for BRCA mutation status in therapeutic trials in ovarian cancer?

Authors
Kauff, ND
MLA Citation
Kauff, ND. "Is It time to stratify for BRCA mutation status in therapeutic trials in ovarian cancer?." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.1 (January 2008): 9-10.
PMID
18165631
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
1
Publish Date
2008
Start Page
9
End Page
10
DOI
10.1200/jco.2007.14.0244

How should women with early-onset endometrial cancer be evaluated for lynch syndrome?

Authors
Kauff, ND
MLA Citation
Kauff, ND. "How should women with early-onset endometrial cancer be evaluated for lynch syndrome?." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 25.33 (November 2007): 5143-5146.
PMID
17925541
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
33
Publish Date
2007
Start Page
5143
End Page
5146
DOI
10.1200/jco.2007.13.4940

Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions.

Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast/Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk ovarian cancer. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2 or MSH6, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancer as well as a 9-12% lifetime risk of ovarian cancer. Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from hereditary cancer risk assessment for Hereditary Breast/Ovarian Cancer and the Lynch/Hereditary Non-Polyposis Colorectal Cancer syndrome.

Authors
Lancaster, JM; Powell, CB; Kauff, ND; Cass, I; Chen, L-M; Lu, KH; Mutch, DG; Berchuck, A; Karlan, BY; Herzog, TJ; Society of Gynecologic Oncologists Education Committee,
MLA Citation
Lancaster, JM, Powell, CB, Kauff, ND, Cass, I, Chen, L-M, Lu, KH, Mutch, DG, Berchuck, A, Karlan, BY, Herzog, TJ, and Society of Gynecologic Oncologists Education Committee, . "Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions." Gynecologic Oncology 107.2 (November 2007): 159-162.
PMID
17950381
Source
epmc
Published In
Gynecologic Oncology
Volume
107
Issue
2
Publish Date
2007
Start Page
159
End Page
162
DOI
10.1016/j.ygyno.2007.09.031

Screening and prevention of hereditary gynecologic cancers.

Endometrial and ovarian cancer are the fourth and fifth most common malignancies in women, with approximately 40,000 new endometrial and 25,000 new ovarian cancers expected to be diagnosed in the Unites States this year. While the majority of these cancers will occur in the absence of a family history, approximately 5% of endometrial cancers and 10% of ovarian cancers will be the result of inherited defects in high-penetrance cancer susceptibility genes. With the identification and subsequent availability of clinical genetic testing for mutations in the genes associated with hereditary breast-ovarian cancer and the Lynch/hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, targeted risk-reduction using intensive screening, chemoprevention, and prophylactic surgery has become possible for women at inherited risk of gynecologic malignancies. We review the options for gynecologic cancer risk reduction in women with an inherited mutation in BRCA1, BRCA2, or one of the mismatch repair (MMR) genes associated with Lynch/HNPCC syndrome. Additionally, we outline ongoing questions and areas for future research.

Authors
Kehoe, SM; Kauff, ND
MLA Citation
Kehoe, SM, and Kauff, ND. "Screening and prevention of hereditary gynecologic cancers." Seminars in Oncology 34.5 (October 2007): 406-410. (Review)
PMID
17920895
Source
epmc
Published In
Seminars in Oncology
Volume
34
Issue
5
Publish Date
2007
Start Page
406
End Page
410
DOI
10.1053/j.seminoncol.2007.07.004

BRCA mutations in women with ductal carcinoma in situ.

PURPOSE: The strength of the association between ductal carcinoma in situ (DCIS) and BRCA mutations has not been defined. EXPERIMENTAL DESIGN: Mutation frequency was compared in three groups: (1) a prevalent series of women with DCIS, (2) an incident series of women with DCIS, and (3) a clinic-based series of women with DCIS referred for hereditary cancer risk assessment. In groups 1 and 2, limited to Ashkenazi Jewish (AJ) cases, mutation frequency was compared with that in age-matched AJ controls with invasive breast cancer (IBC). RESULTS: In group 1, 3 of 62 (4.8%) women with DCIS and 15 of 130 (11.5%) controls with IBC had BRCA mutations. In group 2, 0 of 58 (0%) women with DCIS and 6 of 116 (5.2%) controls with IBC had BRCA mutations [combined odds ratios (OR) in groups 1 and 2: 3.64, 95% confidence interval (95% CI), 1.06-12.46; P=0.04]. In group 3, deleterious mutations were identified in 10 of 79 (12.7%) probands with DCIS, similar to the frequency in IBC probands. In group 3, mutations were associated with family history of ovarian cancer (OR, 13.35; 95% CI, 2.48-71.94; P=0.003) or early onset breast cancer (OR, 16.23; 95% CI, 1.68-157.01; P=0.02) but not with AJ ethnicity or age at diagnosis. CONCLUSIONS: BRCA mutations were less frequent in women with DCIS not selected for family history or age at diagnosis than in women with IBC. Nonetheless, mutations were found in a significant proportion of women with DCIS who presented for hereditary risk assessment.

Authors
Smith, KL; Adank, M; Kauff, N; Lafaro, K; Boyd, J; Lee, JB; Hudis, C; Offit, K; Robson, M
MLA Citation
Smith, KL, Adank, M, Kauff, N, Lafaro, K, Boyd, J, Lee, JB, Hudis, C, Offit, K, and Robson, M. "BRCA mutations in women with ductal carcinoma in situ." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 13.14 (July 2007): 4306-4310.
PMID
17634561
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
14
Publish Date
2007
Start Page
4306
End Page
4310
DOI
10.1158/1078-0432.ccr-07-0146

Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2.

Women with mutations in BRCA1 or BRCA2 are at tremendously increased lifetime risk of both breast and BRCA-associated gynecologic (ovarian, fallopian tube, and primary peritoneal) cancer. Because of limitations in the efficacy of available screening and chemopreventive approaches for women with a mutation in one of these genes, surgical risk reduction, particularly risk-reducing salpingo-oophorectomy (RRSO), has become an important component of the management options in hereditary breast-ovarian cancer syndrome. This article will review the rationale and efficacy of RRSO for prevention of breast and BRCA-associated gynecologic cancer. Surgical technique and methods of pathologic evaluation will be presented. Controversies regarding uterine preservation and post-RRSO hormone replacement therapy will be addressed. Considerations that may impact the appropriate timing of the procedure will be reviewed, and the potential role of RRSO in BRCA-negative hereditary breast cancer families will also be discussed.

Authors
Kauff, ND; Barakat, RR
MLA Citation
Kauff, ND, and Barakat, RR. "Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 25.20 (July 2007): 2921-2927. (Review)
PMID
17617523
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
20
Publish Date
2007
Start Page
2921
End Page
2927
DOI
10.1200/jco.2007.11.3449

Modeling genetic risk of breast cancer.

Authors
Kauff, ND; Offit, K
MLA Citation
Kauff, ND, and Offit, K. "Modeling genetic risk of breast cancer." Jama 297.23 (June 2007): 2637-2639.
PMID
17579233
Source
epmc
Published In
Jama
Volume
297
Issue
23
Publish Date
2007
Start Page
2637
End Page
2639
DOI
10.1001/jama.297.23.2637

Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma.

Identification of the microsatellite instability (MSI) phenotype in endometrial carcinoma is important given that such tumors are the most common noncolorectal tumors to occur in hereditary nonpolyposis colorectal cancer syndrome, and may bear prognostic relevance. The objective of this study was to assess the utility of immunohistochemistry (IHC), a simple and fast technique, in detecting MSI in endometrial carcinoma. The study subjects consisted of 90 endometrial carcinoma patients with equal representation of MSI-high (MSI-H) and non-MSI-H tumors. MSI was tested using the standard polymerase chain reaction-based method and the 5 NCI-recommended markers. Overall, IHC with MLH1 and MSH2 antibodies detected 69% of MSI-H tumors with a specificity of 100%. Adding PMS2 and MSH6 to the antibody panel increased the sensitivity to 91% but decreased the specificity to 83%. The most common IHC abnormality in MSI tumors was concurrent loss of MLH1/PMS2. Assessment of staining was straightforward in most cases but not in all. Staining inadequacies existed. Five stains (4 MLH1 and 1 MSH6) were not interpretable because of the lack of any internal positive control. Two percent to 10% of the cases (depending on the antibody assessed) had only focal weak staining; the highest frequency (10%) occurred with MLH1 antibody. PMS2 staining detected 7 MLH1-staining present MSI-H cases, thus partly accounting for the increased sensitivity with the 4-antibody panel. MSH6 staining identified 9 cases with loss of MSH6 alone, 6 of 9 were non-MSI-H, thus partly accounting for the decreased specificity with the 4-antibody panel. In conclusion, our results suggest that IHC is useful in detecting MSI in endometrial carcinoma. Although IHC has a lower sensitivity with more apparent staining inadequacies in detecting MSI in endometrial carcinoma than it does in colorectal carcinoma, its use in endometrial carcinoma may be an important adjunct when screening for hereditary cases. In the future, as prognostic and therapeutic implications of MSI phenotype become better defined, it may be reasonable to perform IHC for mismatch repair proteins in large numbers of endometrial carcinomas.

Authors
Modica, I; Soslow, RA; Black, D; Tornos, C; Kauff, N; Shia, J
MLA Citation
Modica, I, Soslow, RA, Black, D, Tornos, C, Kauff, N, and Shia, J. "Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma." The American Journal of Surgical Pathology 31.5 (May 2007): 744-751.
PMID
17460459
Source
epmc
Published In
The American Journal of Surgical Pathology
Volume
31
Issue
5
Publish Date
2007
Start Page
744
End Page
751
DOI
10.1097/01.pas.0000213428.61374.06

Does a BRCA mutation plus tamoxifen equal hysterectomy?

Authors
Lu, KH; Kauff, ND
MLA Citation
Lu, KH, and Kauff, ND. "Does a BRCA mutation plus tamoxifen equal hysterectomy?." Gynecologic Oncology 104.1 (January 2007): 3-4.
PMID
17222708
Source
epmc
Published In
Gynecologic Oncology
Volume
104
Issue
1
Publish Date
2007
Start Page
3
End Page
4
DOI
10.1016/j.ygyno.2006.11.015

Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.

BACKGROUND: Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes. METHODS: We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2. Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation. FINDINGS: Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0.56 [95% CI 0.45-0.71]; p<0.0001) and carriers of BRCA2 mutations (0.39 [0.23-0.66]; p=0.0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0.67 [0.46-0.96]; p=0.03), but with an increased risk for those with BRCA2 mutations (2.74 [1.18-6.41]; p=0.02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0.74 [0.56-0.97]; p=0.03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0.72 [0.41-1.29]; p=0.27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0.80 [0.59-1.08]; p=0.15), or for carriers of BRCA2 mutations (0.63 [0.34-1.15]; p=0.13). INTERPRETATION: Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.

Authors
McLaughlin, JR; Risch, HA; Lubinski, J; Moller, P; Ghadirian, P; Lynch, H; Karlan, B; Fishman, D; Rosen, B; Neuhausen, SL; Offit, K; Kauff, N; Domchek, S; Tung, N; Friedman, E; Foulkes, W; Sun, P; Narod, SA; Hereditary Ovarian Cancer Clinical Study Group,
MLA Citation
McLaughlin, JR, Risch, HA, Lubinski, J, Moller, P, Ghadirian, P, Lynch, H, Karlan, B, Fishman, D, Rosen, B, Neuhausen, SL, Offit, K, Kauff, N, Domchek, S, Tung, N, Friedman, E, Foulkes, W, Sun, P, Narod, SA, and Hereditary Ovarian Cancer Clinical Study Group, . "Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study." The Lancet. Oncology 8.1 (January 2007): 26-34.
PMID
17196508
Source
epmc
Published In
The Lancet. Oncology
Volume
8
Issue
1
Publish Date
2007
Start Page
26
End Page
34
DOI
10.1016/s1470-2045(06)70983-4

Effect of mammography on breast cancer risk in women with mutations in BRCA1 or BRCA2.

Women who carry mutations in either the BRCA1 or BRCA2 genes are at risk for early-onset breast cancer and are recommended to begin screening mammography at age 25 to 30 years. Results of in vitro and animal studies suggest that BRCA1/BRCA2 mutation carriers are hypersensitive to ionizing radiation and possibly to radiation-induced breast cancer. This study was undertaken to investigate the association of low-dose radiation exposure from mammograms with breast cancer status in BRCA mutation carriers. One hundred sixty-two female mutation carriers provided information at time of genetic testing about exposure to mammograms before enrollment. Using unconditional logistic regression, breast cancer status was not associated with number of mammograms received before diagnosis (affected women) or ascertainment [unaffected women; adjusted odds ratio (OR), 0.94; P = not significant]. A larger group of 213 women provided information about lifetime number of mammograms. There was no association between mammogram exposure and risk in the group as a whole (adjusted OR, 1.04; P = not significant), although there was a modest association in BRCA1 carriers (adjusted OR, 1.08; P = 0.03). These findings indicate that screening mammography is unlikely to be associated with a large increase in breast cancer risk in this population.

Authors
Goldfrank, D; Chuai, S; Bernstein, JL; Ramon Y Cajal, T; Lee, JB; Alonso, MC; Diez, O; Baiget, M; Kauff, ND; Offit, K; Robson, M
MLA Citation
Goldfrank, D, Chuai, S, Bernstein, JL, Ramon Y Cajal, T, Lee, JB, Alonso, MC, Diez, O, Baiget, M, Kauff, ND, Offit, K, and Robson, M. "Effect of mammography on breast cancer risk in women with mutations in BRCA1 or BRCA2." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 15.11 (November 2006): 2311-2313.
PMID
17119064
Source
epmc
Published In
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
Volume
15
Issue
11
Publish Date
2006
Start Page
2311
End Page
2313
DOI
10.1158/1055-9965.epi-06-0176

The significance of cytological mesothelial atypia diagnosed from peritoneal washings performed during risk-reducing salpingo-oophorectomy.

OBJECTIVE: Occult cancer may be found in a small proportion of women undergoing risk-reducing salpingo-oophorectomy (RRSO). However, the results and significance of peritoneal wash cytology in this setting are not clear. The objective of this study was to determine the significance of cytologic mesothelial atypia in the peritoneal washings of patients undergoing RRSO. METHODS: We conducted a retrospective chart review of all patients undergoing RRSO from July 2002 to December 2003. Patient charts were reviewed for information regarding cytology, pathology, demographics, surgical procedure and findings, and outcome. RESULTS: One hundred thirty women underwent RRSO during the study period. One hundred seventeen had washings performed during the procedure and constitute the study cohort. The median age at the time of the procedure was 48 years (range, 33-78 years). Final cytology was reported as normal in 102 patients (87%), mesothelial atypia in 13 (11%), and non-satisfactory in 2 (2%). Ovarian and tubal histopathology was normal in all cases. No association was found between mesothelial atypia and age, prior breast cancer, or prior abdominal surgery. Twenty-nine patients had previously undergone genetic testing for BRCA1/2 mutations as part of ongoing prospective follow-up studies. Four (24%) of 17 patients with a known BRCA1 or BRCA2 mutation were found to have mesothelial atypia compared to 1 (8%) of 12 with no mutation. With a median follow-up time of 20 months (range, 1-40 months), none of the patients with mesothelial atypia were diagnosed with peritoneal malignancy following RRSO. CONCLUSION: In this study, mesothelial atypia was identified in 11% of patients who had peritoneal washings performed at the time of RRSO. No patients with mesothelial atypia went on to develop peritoneal carcinoma. The link between mesothelial atypia and mutations in BRCA1/2 and the need to perform peritoneal washings in this setting are both yet to be determined.

Authors
Eitan, R; Soslow, R; Lin, O; Kauff, ND; Liu, L; Barakat, RR; Chi, DS
MLA Citation
Eitan, R, Soslow, R, Lin, O, Kauff, ND, Liu, L, Barakat, RR, and Chi, DS. "The significance of cytological mesothelial atypia diagnosed from peritoneal washings performed during risk-reducing salpingo-oophorectomy." Gynecologic Oncology 102.2 (August 2006): 315-318.
PMID
16430946
Source
epmc
Published In
Gynecologic Oncology
Volume
102
Issue
2
Publish Date
2006
Start Page
315
End Page
318
DOI
10.1016/j.ygyno.2005.12.021

Reducing the risk of gynecologic cancer in the Lynch syndrome.

Authors
Offit, K; Kauff, ND
MLA Citation
Offit, K, and Kauff, ND. "Reducing the risk of gynecologic cancer in the Lynch syndrome." The New England Journal of Medicine 354.3 (January 2006): 293-295.
PMID
16421372
Source
epmc
Published In
The New England Journal of Medicine
Volume
354
Issue
3
Publish Date
2006
Start Page
293
End Page
295
DOI
10.1056/nejme058284

Accuracy of BRCA1 and BRCA2 founder mutation analysis in formalin-fixed and paraffin-embedded (FFPE) tissue.

A major limitation in counseling unaffected women from families with inherited breast and ovarian cancer is that a "true-negative" interpretation of wild type BRCA analysis of the proband cannot be inferred in the absence of demonstration of a BRCA mutation segregating in the kindred. Documentation of familial BRCA mutations from paraffin-derived DNA of deceased patients has been limited due to reports of technical complications leading to lack of reproducibility of BRCA testing of archival material.DNA was extracted from formalin-fixed paraffin-embedded (FFPE) morphologically normal tissue of 161 blinded, coded samples from women previously genotyped for the three Ashkenazi Jewish BRCA founder mutations from lymphocyte-derived DNA. Multiplex PCR followed by denaturing polyacrylamide gel electrophoresis was performed for the three founder mutations to determine if analysis on FFPE tissue could produce results concordant with those of the lymphocyte-derived DNA.After disclosure of the sample codes, the results were compared with the original lymphocyte-derived DNA genotypes. Excluding one sample unevaluable due to PCR failure, there was 100% concordance of 160 genotypes (120 mutation samples) derived from DNA from archival FFPE tissue compared to peripheral lymphocytes.The method described reliably detected BRCA founder mutations in archival DNA derived from FFPE tissue. These results suggests that this technique may be useful in clinical settings to inform wild type BRCA results of unaffected probands, leading to avoidance of unnecessary intensified surveillance or risk-reducing surgery. With further validation this approach can also be applied to other populations where founder mutations are observed.

Authors
Adank, MA; Brogi, E; Bogomolniy, F; Wadsworth, EA; Lafaro, KJ; Yee, CJ; Kirchhoff, T; Meijers-Heijboer, EJ; Kauff, ND; Boyd, J; Offit, K
MLA Citation
Adank, MA, Brogi, E, Bogomolniy, F, Wadsworth, EA, Lafaro, KJ, Yee, CJ, Kirchhoff, T, Meijers-Heijboer, EJ, Kauff, ND, Boyd, J, and Offit, K. "Accuracy of BRCA1 and BRCA2 founder mutation analysis in formalin-fixed and paraffin-embedded (FFPE) tissue." Familial Cancer 5.4 (January 2006): 337-342.
PMID
16724247
Source
epmc
Published In
Familial Cancer
Volume
5
Issue
4
Publish Date
2006
Start Page
337
End Page
342
DOI
10.1007/s10689-006-0003-y

Laparoscopic bilateral salpingo-oophorectomy in breast cancer patients after transverse rectus abdominus myocutaneous flap reconstructive surgery.

OBJECTIVE: The aim of this study was to describe the feasibility and outcome of laparoscopic risk-reducing salpingo-oophorectomy (RRSO) in patients with a history of breast cancer who previously had undergone a transverse rectus abdominus myocutaneous (TRAM) flap reconstruction. METHODS: We performed a retrospective review of patients with a history of breast cancer who had undergone laparoscopic RRSO between February 1995 and April 2002. Patients who had undergone TRAM flap reconstructive surgery were compared with patients who had undergone laparoscopic RRSO without prior reconstructive surgery. RESULTS: We identified 102 patients with a history of breast cancer who were candidates for a laparoscopic RRSO during the study period. One hundred one of these patients underwent the procedure, including 10 patients with a history of TRAM flap breast reconstructive surgery. One patient did not undergo the procedure because she was noted to be hypotensive prior to the procedure from her bowel preparation. There were no differences between the groups with or without prior history of TRAM flap reconstruction with respect to body mass index, prior abdominal surgery, menopausal status, or preoperative ultrasound characteristics. Operatively, there was no difference between the groups with respect to estimated blood loss, hospital stay, and intraoperative and postoperative complication rates. The only noted difference between the two groups was the estimated operating time (TRAM group, 91 min; non-TRAM group, 70 min [P<0.01]). CONCLUSIONS: Laparoscopic RRSO is safe and feasible in patients who have undergone a prior TRAM flap reconstruction.

Authors
Awtrey, CS; Abu-Rustum, NR; Disa, JJ; Ivy, JJ; Kauff, ND; Hummer, AJ; Barakat, RR
MLA Citation
Awtrey, CS, Abu-Rustum, NR, Disa, JJ, Ivy, JJ, Kauff, ND, Hummer, AJ, and Barakat, RR. "Laparoscopic bilateral salpingo-oophorectomy in breast cancer patients after transverse rectus abdominus myocutaneous flap reconstructive surgery." Gynecologic Oncology 99.3 (December 2005): 720-725.
PMID
16169063
Source
epmc
Published In
Gynecologic Oncology
Volume
99
Issue
3
Publish Date
2005
Start Page
720
End Page
725
DOI
10.1016/j.ygyno.2005.07.120

Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families.

Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.

Authors
Kauff, ND; Mitra, N; Robson, ME; Hurley, KE; Chuai, S; Goldfrank, D; Wadsworth, E; Lee, J; Cigler, T; Borgen, PI; Norton, L; Barakat, RR; Offit, K
MLA Citation
Kauff, ND, Mitra, N, Robson, ME, Hurley, KE, Chuai, S, Goldfrank, D, Wadsworth, E, Lee, J, Cigler, T, Borgen, PI, Norton, L, Barakat, RR, and Offit, K. "Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families." Journal of the National Cancer Institute 97.18 (September 2005): 1382-1384.
PMID
16174860
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
97
Issue
18
Publish Date
2005
Start Page
1382
End Page
1384
DOI
10.1093/jnci/dji281

Ovarian carcinoma screening in women at intermediate risk: impact on quality of life and need for invasive follow-up.

BACKGROUND: Women with family histories suggestive of an increased risk of ovarian carcinoma who have not had a deleterious BRCA1 or BRCA2 mutation identified are commonly suggested to consider ovarian carcinoma screening with transvaginal ultrasound and/or assessment of CA 125 levels. Limited information is available regarding the impact of this approach on either quality of life (QOL) or need for invasive follow-up in this group of women. METHODS: From November 1999 to October 2002, 184 women at intermediate risk of ovarian carcinoma were enrolled in a prospective study. Participants were screened with twice yearly transvaginal ultrasound and CA 125 assessments. Impact on QOL was measured using the Mental Component Summary (MCS) score of the Medical Outcomes Studies Short Form-36. Need for invasive follow-up was determined by questionnaire and medical record review. RESULTS: In the current study, 135 participants underwent > or = 1 follow-up assessment. During a mean of 19.8 months of follow-up, 12.9% of ultrasounds and 3.8% of CA 125 assessments were abnormal. The authors reported that 38.5% of participants had > or = 1 abnormal ovarian screen that required a short interval follow-up. Because of either abnormal bleeding or ultrasound abnormalities, 24% of participants underwent > or = 1 endometrial sampling. Controlling for a history of breast carcinoma and menopausal status, abnormal ovarian screening results were associated with a decrease in MCS score (P = 0.034), whereas the need for endometrial sampling was not (P = 0.87). CONCLUSIONS: Ovarian carcinoma screening in women at intermediate risk was associated with a substantial rate of abnormal screen results, endometrial sampling, and in women with abnormal ovarian screening findings, a decrease in MCS scores. These findings may have important implications for women considering ovarian carcinoma screening and for the design of future ovarian carcinoma screening trials.

Authors
Kauff, ND; Hurley, KE; Hensley, ML; Robson, ME; Lev, G; Goldfrank, D; Castiel, M; Brown, CL; Ostroff, JS; Hann, LE; Offit, K; Barakat, RR
MLA Citation
Kauff, ND, Hurley, KE, Hensley, ML, Robson, ME, Lev, G, Goldfrank, D, Castiel, M, Brown, CL, Ostroff, JS, Hann, LE, Offit, K, and Barakat, RR. "Ovarian carcinoma screening in women at intermediate risk: impact on quality of life and need for invasive follow-up." Cancer 104.2 (July 2005): 314-320.
PMID
15948173
Source
epmc
Published In
Cancer
Volume
104
Issue
2
Publish Date
2005
Start Page
314
End Page
320
DOI
10.1002/cncr.21148

The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds.

Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms occurring at young age. Germline mutations in the TP53 tumor suppressor gene have been identified in approximately 71 of LFS patients and 22 of Li-Fraumeni-like (LFL) patients. Mutations within the cell cycle checkpoint gene CHEK2 have also been reported in some patients with LFS, LFL, and phenotypically suggestive of LFS (PS-LFS) not carrying a TP53 mutation. In this study, we show that 7 of the 23 patients with LFS/LFL tested positive for deleterious mutations in p53. Fifteen of the remaining sixteen were not found to carry the CHEK2* 1100delCmutation. These results indicate that CHEK2*1100delC is not a common cause of LFS, LFL, or PS-LFS in North American kindreds not carrying a TP53 mutation. Of note, two patients were found to carry p53* R72P, which is of unknown clinical significance. Lack of segregation of this allele in one of these kindreds provides strong evidence that the R72P allele is not disease-causing. While mutations in p53 account for a proportion of patients with LFS/LFL, future studies are needed to determine if other genes are responsible for LFS/LFL families not carrying germline p53 mutations.

Authors
Siddiqui, R; Onel, K; Facio, F; Nafa, K; Diaz, LR; Kauff, N; Huang, H; Robson, M; Ellis, N; Offit, K
MLA Citation
Siddiqui, R, Onel, K, Facio, F, Nafa, K, Diaz, LR, Kauff, N, Huang, H, Robson, M, Ellis, N, and Offit, K. "The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds." Familial Cancer 4.2 (January 2005): 177-181.
PMID
15951970
Source
epmc
Published In
Familial Cancer
Volume
4
Issue
2
Publish Date
2005
Start Page
177
End Page
181
DOI
10.1007/s10689-004-1946-5

Early detection and prognosis of ovarian cancer using serum YKL-40.

YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer.Serum YKL-40 levels were assayed by enzyme-linked immunosorbent assay for 46 healthy subjects, 61 high-risk individuals, 33 patients with benign gynecologic processes, and 50 preoperative patients subsequently diagnosed with predominantly early-stage ovarian cancer. Serum CA125 and CA15-3 values were obtained.Median YKL-40 level was 28 ng/mL (range, 15 to 166 ng/mL) for healthy subjects, 36 ng/mL (range, 9 to 69 ng/mL) for high-risk individuals without prior cancer, 44.5 ng/mL (range, 5 to 133 ng/mL) for high-risk patients with prior breast cancer, and 38 ng/mL (range, 5 to 67 ng/mL) for individuals with benign gynecologic processes (P = NS). Median preoperative YKL-40 level for ovarian cancer patients was 94 ng/mL (range, 17 to 517 ng/mL; P <.0001 compared with normal and high-risk). YKL-40 was elevated (>/= 62 ng/mL) in 36 (72%) of 50 patients compared with 23 (46%) of 50 and 13 (26%) of 50 patients for CA125 and CA15-3 (P <.008). Twenty (65%) of 31 early-stage patients had elevated serum YKL-40 levels compared with 11 (35%) of 31 and four (13%) of 31 patients for CA125 and CA15-3 (P =.039). YKL-40 levels increased with stage (P <.005), regardless of grade, histology, or patient age. Patients with early-stage tumors with YKL-40 values more than 80 ng/mL had a worse prognosis (71% recurrence v no recurrence [P =.034]).YKL-40 may represent a novel marker for the detection of early-stage ovarian cancer. YKL-40 levels in early-stage patients may also predict disease recurrence and survival. The utility of YKL-40 in detection of early-stage ovarian cancer deserves further investigation.

Authors
Dupont, J; Tanwar, MK; Thaler, HT; Fleisher, M; Kauff, N; Hensley, ML; Sabbatini, P; Anderson, S; Aghajanian, C; Holland, EC; Spriggs, DR
MLA Citation
Dupont, J, Tanwar, MK, Thaler, HT, Fleisher, M, Kauff, N, Hensley, ML, Sabbatini, P, Anderson, S, Aghajanian, C, Holland, EC, and Spriggs, DR. "Early detection and prognosis of ovarian cancer using serum YKL-40." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 22.16 (August 2004): 3330-3339.
PMID
15310777
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
22
Issue
16
Publish Date
2004
Start Page
3330
End Page
3339
DOI
10.1200/jco.2004.09.112

Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation.

The management of uterine bleeding in female transplant patients over a 3-year period at our institution was reviewed. A total of 33 females who had undergone allogeneic hematopoietic stem cell transplant were identified as having received gynecologic consultation for the diagnosis of menorrhagia. Hormone therapy achieved a resolution of symptoms in 32 (97%) of the patients, and 26 (79%) required only one hormone regimen. Following resolution of symptoms, transition to standard-dose oral contraceptive pills as maintenance therapy prevented recurrent menorrhagia due to high circulating estrogen levels. Alternatives for patients who are unable to tolerate oral administration and those with hepatotoxicity are also discussed.

Authors
Amsterdam, A; Jakubowski, A; Castro-Malaspina, H; Baxi, E; Kauff, N; Krychman, M; Stier, E; Castiel, M
MLA Citation
Amsterdam, A, Jakubowski, A, Castro-Malaspina, H, Baxi, E, Kauff, N, Krychman, M, Stier, E, and Castiel, M. "Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation." Bone Marrow Transplantation 34.4 (August 2004): 363-366.
PMID
15195079
Source
epmc
Published In
Bone Marrow Transplantation
Volume
34
Issue
4
Publish Date
2004
Start Page
363
End Page
366
DOI
10.1038/sj.bmt.1704577

Surgical risk-reduction in carriers of BRCA mutations: where do we go from here?

Authors
Kauff, ND; Barakat, RR
MLA Citation
Kauff, ND, and Barakat, RR. "Surgical risk-reduction in carriers of BRCA mutations: where do we go from here?." Gynecologic Oncology 93.2 (May 2004): 277-279.
PMID
15099933
Source
epmc
Published In
Gynecologic Oncology
Volume
93
Issue
2
Publish Date
2004
Start Page
277
End Page
279
DOI
10.1016/j.ygyno.2004.03.016

BRCA mutations and risk of prostate cancer in Ashkenazi Jews.

PURPOSE: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study. EXPERIMENTAL DESIGN: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age. RESULTS: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64-7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased. CONCLUSIONS: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

Authors
Kirchhoff, T; Kauff, ND; Mitra, N; Nafa, K; Huang, H; Palmer, C; Gulati, T; Wadsworth, E; Donat, S; Robson, ME; Ellis, NA; Offit, K
MLA Citation
Kirchhoff, T, Kauff, ND, Mitra, N, Nafa, K, Huang, H, Palmer, C, Gulati, T, Wadsworth, E, Donat, S, Robson, ME, Ellis, NA, and Offit, K. "BRCA mutations and risk of prostate cancer in Ashkenazi Jews." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 10.9 (May 2004): 2918-2921.
PMID
15131025
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
10
Issue
9
Publish Date
2004
Start Page
2918
End Page
2921
DOI
10.1158/1078-0432.ccr-03-0604

Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations

Authors
Kauff, ND; Brogi, E; Scheuer, L; Adem, C; Hartmann, LC
MLA Citation
Kauff, ND, Brogi, E, Scheuer, L, Adem, C, and Hartmann, LC. "Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations." Breast Diseases 15.1 (April 1, 2004): 59-null.
Source
scopus
Published In
Breast Diseases
Volume
15
Issue
1
Publish Date
2004
Start Page
59

Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer

Authors
Kirchhoff, T; Satagopan, JM; Kauff, ND; Huang, H; Kolachana, P; Palmer, C; Rapaport, H; Nafa, K; Ellis, NA; Offit, K
MLA Citation
Kirchhoff, T, Satagopan, JM, Kauff, ND, Huang, H, Kolachana, P, Palmer, C, Rapaport, H, Nafa, K, Ellis, NA, and Offit, K. "Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer." Journal of the National Cancer Institute 96.1 (January 7, 2004): 68-70. (Academic Article)
Source
wos
Published In
Journal of the National Cancer Institute
Volume
96
Issue
1
Publish Date
2004
Start Page
68
End Page
70
DOI
10.1093/jnci.djh006

Hereditary ovarian cancer in Ashkenazi Jews.

Ovarian cancer is the fourth leading cause of cancer deaths among American women. While women in both the Ashkenazi and non-Ashkenazi populations have an estimated 1.7% lifetime risk of acquiring malignancy, the proportion of hereditary ovarian cancer is much higher in the Ashkenazim. Most of this increased proportion of hereditary ovarian cancer risk is accounted for by inherited mutations in the BRCA1 and BRCA2 genes. In the Ashkenazi Jewish population, 29 to 41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in BRCA 1 and BRCA 2, while only 10% of ovarian cancer is attributed to mutations of these genes in non-Ashkenazim. In the US population in general, it is estimated that between 1 out of 345 and 1 out of 1000 individuals carries a BRCA mutation, compared with approximately 1 in 40 individuals of Ashkenazi Jewish descent. The ovarian cancer risk up to age 70 associated with BRCA mutation carriers has been reported to be as high as 66% for BRCA1 and 27% for BRCA2 mutation carriers. Ovarian cancer in Ashkenazi kindreds has served as a model for the study of the histopathology of inherited ovarian cancers as well as for the study of risk reduction and screening among all women at inherited risk of ovarian cancer.

Authors
Robles-Díaz, L; Goldfrank, DJ; Kauff, ND; Robson, M; Offit, K
MLA Citation
Robles-Díaz, L, Goldfrank, DJ, Kauff, ND, Robson, M, and Offit, K. "Hereditary ovarian cancer in Ashkenazi Jews." Familial Cancer 3.3-4 (January 2004): 259-264. (Review)
PMID
15516850
Source
epmc
Published In
Familial Cancer
Volume
3
Issue
3-4
Publish Date
2004
Start Page
259
End Page
264
DOI
10.1007/s10689-004-9552-0

Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer.

Mutations in BRCA1 and BRCA2 that predispose to breast and ovarian cancer are detected in approximately 2.5% of the Ashkenazi Jewish population. To explore whether carriers of Ashkenazi founder mutations in BRCA1 or BRCA2 have an increased risk for colorectal cancer, we screened 586 unselected Ashkenazi Jewish case patients with colorectal cancer for the three common founder mutations in BRCA1 and BRCA2. We identified six carriers (1.02%) among these case patients. After adjusting for age at diagnosis and sex by use of logistic regression analysis, we compared the incidence of carriers in this group of 586 case patients with that of 5012 Ashkenazi Jewish control subjects without a known history of colorectal cancer. The presence of a founder BRCA mutation was not associated with the risk of colorectal cancer (relative risk = 0.50, 95% confidence interval = 0.22 to 1.14). We thus recommend that counseling for colorectal cancer screening and prevention in individuals with BRCA mutations be based on the personal and family history of colorectal cancer or associated syndromic malignancies.

Authors
Kirchhoff, T; Satagopan, JM; Kauff, ND; Huang, H; Kolachana, P; Palmer, C; Rapaport, H; Nafa, K; Ellis, NA; Offit, K
MLA Citation
Kirchhoff, T, Satagopan, JM, Kauff, ND, Huang, H, Kolachana, P, Palmer, C, Rapaport, H, Nafa, K, Ellis, NA, and Offit, K. "Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer." Jnci Journal of the National Cancer Institute 96.1 (January 2004): 68-70.
PMID
14709740
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
96
Issue
1
Publish Date
2004
Start Page
68
End Page
70
DOI
10.1093/jnci/djh006

Pre- and postmenopausal high-risk women undergoing screening for ovarian cancer: anxiety, risk perceptions, and quality of life.

OBJECTIVE: Recommendations for women at high risk of ovarian cancer include prophylactic salpingo-oophorectomy (PSO) or screening with transvaginal ultrasonography (TVUS) and CA125 levels. The best strategy for improving survival and maintaining quality of life in high-risk women is not known. Premenopausal women may be more reluctant than postmenopausal women to undergo PSO. However, the risk of false-positive screening results may be more likely in premenopausal women, posing potential psychological risk for those enrolled in high-risk ovarian cancer surveillance programs. We sought to determine whether anxiety, depression, perception of ovarian cancer risk, and false-positive test frequency differed between high-risk premenopausal and postmenopausal women initiating ovarian cancer screening. METHODS: High-risk women aged > or = 30 years enrolling in a TVUS plus CA125 ovarian cancer screening study completed standard QOL (SF-36), cancer-specific anxiety (IES), depression (CES-D), and ovarian cancer risk perception measures. CA125 > 35 and TVUS showing solid or complex cystic ovarian masses were considered abnormal. Abnormal tests were repeated after 4-6 weeks. Persistently abnormal tests prompted a search for malignancy. Tests that normalized on repeat were considered false positive. RESULTS: One hundred forty-seven high-risk women, median age 46 (range, 30-78), 78 premenopausal and 69 postmenopausal, had > or = 1 TVUS/CA125/outcome assessment. Premenopausal women were more likely than postmenopausal women to consider themselves at higher risk of ovarian cancer compared with women their age (P < 0.001) and compared with women with similar family histories (P < 0.001). Mean personal perception of lifetime risk of ovarian cancer among premenopausal women was 37% (range, 0-90%) versus 26% (range, 0-60%) among postmenopausal women (P = 0.02). While general QOL and depression scores were similar, 38% of premenopausal women reported high anxiety versus 27% of postmenopausal women (P = 0.03). Thirty percent of women required repeat CA125 or TVUS after first screening; 10.8% of premenopausal women versus 4.6% of postmenopausal women required repeat CA125; and 23.3% of premenopausal and 20.6% of postmenopausal women required repeat TVUS. One postmenopausal woman with persistently rising CA125 >100 had negative mammography, colonoscopy, and dilation and curettage/bilateral salpingo-oophorectomy. All other abnormal tests normalized on repeat. Two premenopausal women withdrew due to anxiety following false-positive CA125 results. Five women (2 premenopausal, 3 postmenopausal) with normal TVUS/CA125 screening tests elected PSO, with benign findings. CONCLUSION: Premenopausal women perceive their ovarian cancer risk to be higher, report greater ovarian cancer risk-related anxiety, and are more likely to have false-positive screening results than postmenopausal women. Few high-risk women elect PSO in the short term. Knowledge of the frequency of false-positive screening results and psychosocial outcomes is important for high-risk women choosing strategies for managing ovarian cancer risk.

Authors
Hensley, ML; Robson, ME; Kauff, ND; Korytowsky, B; Castiel, M; Ostroff, J; Hurley, K; Hann, LE; Colon, J; Spriggs, D
MLA Citation
Hensley, ML, Robson, ME, Kauff, ND, Korytowsky, B, Castiel, M, Ostroff, J, Hurley, K, Hann, LE, Colon, J, and Spriggs, D. "Pre- and postmenopausal high-risk women undergoing screening for ovarian cancer: anxiety, risk perceptions, and quality of life." Gynecologic Oncology 89.3 (June 2003): 440-446.
PMID
12798709
Source
epmc
Published In
Gynecologic Oncology
Volume
89
Issue
3
Publish Date
2003
Start Page
440
End Page
446
DOI
10.1016/s0090-8258(03)00147-1

Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations.

BACKGROUND: It has been suggested that BRCA-associated breast carcinoma may often lack a detectable preinvasive phase. To investigate this hypothesis, the authors compared the prevalence of histopathologic lesions in prophylactic mastectomy (PM) specimens from women with BRCA mutations and in mastectomy specimens obtained at autopsy from an age and race-matched comparison group without a known cancer predisposition. METHODS: All specimens from women with a deleterious BRCA1 or BRCA2 mutation who participated in an ongoing follow-up study and underwent PM at Memorial Sloan-Kettering Cancer Center between November 1, 1987 and May 31, 2001 were reviewed. For each case, breast tissue from two age and race-matched women without a known cancer predisposition was also reviewed. The prevalence of benign, premalignant, and cancerous lesions was compared. RESULTS: Mastectomy specimens from 24 cases and 48 comparison subjects were reviewed. Ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH) were all more common in PM specimens from women with BRCA mutations than in those from the comparison group. The odds ratio for the detection of any high-risk lesion (DCIS, lobular carcinoma in situ, ADH, or ALH) in specimens from BRCA mutation carriers was 12.7 (95% confidence interval, 3.1-52.4; P < 0.001). CONCLUSIONS: Lesions associated with an increased risk of subsequent malignancy are more common in PM specimens from women with BRCA mutations than in breast tissue obtained at autopsy from unaffected women without a known predisposition. This finding suggests that hereditary breast carcinoma has a preinvasive phase that may be detectable with aggressive surveillance.

Authors
Kauff, ND; Brogi, E; Scheuer, L; Pathak, DR; Borgen, PI; Hudis, CA; Offit, K; Robson, ME
MLA Citation
Kauff, ND, Brogi, E, Scheuer, L, Pathak, DR, Borgen, PI, Hudis, CA, Offit, K, and Robson, ME. "Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations." Cancer 97.7 (April 2003): 1601-1608.
PMID
12655515
Source
epmc
Published In
Cancer
Volume
97
Issue
7
Publish Date
2003
Start Page
1601
End Page
1608
DOI
10.1002/cncr.11225

Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers.

PURPOSE: In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers. EXPERIMENTAL DESIGN: Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region. RESULTS: No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases. CONCLUSIONS: Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.

Authors
Offit, K; Gilad, S; Paglin, S; Kolachana, P; Roisman, LC; Nafa, K; Yeugelewitz, V; Gonzales, M; Robson, M; McDermott, D; Pierce, HH; Kauff, ND; Einat, P; Jhanwar, S; Satagopan, JM; Oddoux, C; Ellis, N; Skaliter, R; Yahalom, J
MLA Citation
Offit, K, Gilad, S, Paglin, S, Kolachana, P, Roisman, LC, Nafa, K, Yeugelewitz, V, Gonzales, M, Robson, M, McDermott, D, Pierce, HH, Kauff, ND, Einat, P, Jhanwar, S, Satagopan, JM, Oddoux, C, Ellis, N, Skaliter, R, and Yahalom, J. "Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 8.12 (December 2002): 3813-3819.
PMID
12473594
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
8
Issue
12
Publish Date
2002
Start Page
3813
End Page
3819

Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

PURPOSE: Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations. EXPERIMENTAL DESIGN: A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer. RESULTS: Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation. CONCLUSIONS: The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.

Authors
Satagopan, JM; Boyd, J; Kauff, ND; Robson, M; Scheuer, L; Narod, S; Offit, K
MLA Citation
Satagopan, JM, Boyd, J, Kauff, ND, Robson, M, Scheuer, L, Narod, S, and Offit, K. "Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 8.12 (December 2002): 3776-3781.
PMID
12473589
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
8
Issue
12
Publish Date
2002
Start Page
3776
End Page
3781

Estrogen receptor-beta expression in hereditary breast cancer.

Authors
Daidone, MG; Veneroni, S; Cappelletti, V; Radice, P; Pierotti, MA; Younes, M
MLA Citation
Daidone, MG, Veneroni, S, Cappelletti, V, Radice, P, Pierotti, MA, and Younes, M. "Estrogen receptor-beta expression in hereditary breast cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 20.17 (September 2002): 3752-3753. (Letter)
PMID
12202682
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
20
Issue
17
Publish Date
2002
Start Page
3752
End Page
3753
DOI
10.1200/jco.2002.99.116

Oophorectomy in carriers of BRCA mutations.

Authors
Zhuang, SH; Leonard, GD; Swain, SM
MLA Citation
Zhuang, SH, Leonard, GD, and Swain, SM. "Oophorectomy in carriers of BRCA mutations." The New England Journal of Medicine 347.13 (September 2002): 1037-1040. (Letter)
PMID
12324566
Source
epmc
Published In
The New England Journal of Medicine
Volume
347
Issue
13
Publish Date
2002
Start Page
1037
End Page
1040
DOI
10.1056/nejm200209263471317

Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families.

Authors
Kauff, ND; Perez-Segura, P; Robson, ME; Scheuer, L; Siegel, B; Schluger, A; Rapaport, B; Frank, TS; Nafa, K; Ellis, NA; Parmigiani, G; Offit, K
MLA Citation
Kauff, ND, Perez-Segura, P, Robson, ME, Scheuer, L, Siegel, B, Schluger, A, Rapaport, B, Frank, TS, Nafa, K, Ellis, NA, Parmigiani, G, and Offit, K. "Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families." Journal of Medical Genetics 39.8 (August 2002): 611-614. (Letter)
PMID
12161607
Source
epmc
Published In
Journal of Medical Genetics
Volume
39
Issue
8
Publish Date
2002
Start Page
611
End Page
614
DOI
10.1136/jmg.39.8.611

Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. METHODS: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan-Meier analysis and a Cox proportional-hazards model. RESULTS: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). CONCLUSIONS: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer.

Authors
Kauff, ND; Satagopan, JM; Robson, ME; Scheuer, L; Hensley, M; Hudis, CA; Ellis, NA; Boyd, J; Borgen, PI; Barakat, RR; Norton, L; Castiel, M; Nafa, K; Offit, K
MLA Citation
Kauff, ND, Satagopan, JM, Robson, ME, Scheuer, L, Hensley, M, Hudis, CA, Ellis, NA, Boyd, J, Borgen, PI, Barakat, RR, Norton, L, Castiel, M, Nafa, K, and Offit, K. "Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation." The New England Journal of Medicine 346.21 (May 20, 2002): 1609-1615.
PMID
12023992
Source
epmc
Published In
The New England Journal of Medicine
Volume
346
Issue
21
Publish Date
2002
Start Page
1609
End Page
1615
DOI
10.1056/nejmoa020119

Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers.

To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer.Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians.Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing.This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Authors
Scheuer, L; Kauff, N; Robson, M; Kelly, B; Barakat, R; Satagopan, J; Ellis, N; Hensley, M; Boyd, J; Borgen, P; Norton, L; Offit, K
MLA Citation
Scheuer, L, Kauff, N, Robson, M, Kelly, B, Barakat, R, Satagopan, J, Ellis, N, Hensley, M, Boyd, J, Borgen, P, Norton, L, and Offit, K. "Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 20.5 (March 2002): 1260-1268.
PMID
11870168
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
20
Issue
5
Publish Date
2002
Start Page
1260
End Page
1268
DOI
10.1200/jco.20.5.1260

Insurance reimbursement for risk-reducing mastectomy and oophorectomy in women with BRCA1 or BRCA2 mutations.

PURPOSE: Risk-reducing surgery is an important option for women with BRCA1 and BRCA2 mutations. There are reports in the literature that insurance reimbursement for these procedures varies greatly. Because health insurance coverage significantly affects medical decision-making, current information regarding reimbursement practices of third-party payers is needed. METHODS: Retrospective study of hospital billing records of 38 women with documented BRCA1 or BRCA2 mutations who underwent either a risk-reducing mastectomy or a risk-reducing oophorectomy between March 1, 1997, and July 30, 2000. RESULTS: Complete billing and reimbursement information was available for 35 women undergoing a total of 39 risk-reducing surgeries. A total of 38 of 39 (97%) risk-reducing surgeries were covered in full, less applicable coinsurance and deductibles. The rate of insurance reimbursement did not vary with type of insurance, personal history of cancer, or type of procedure. CONCLUSION: Insurance carriers reimbursed the vast majority of BRCA mutation carriers undergoing risk-reducing surgery.

Authors
Kauff, ND; Scheuer, L; Robson, ME; Glogowski, E; Kelly, B; Barakat, R; Heerdt, A; Borgen, PI; Davis, JG; Offit, K
MLA Citation
Kauff, ND, Scheuer, L, Robson, ME, Glogowski, E, Kelly, B, Barakat, R, Heerdt, A, Borgen, PI, Davis, JG, and Offit, K. "Insurance reimbursement for risk-reducing mastectomy and oophorectomy in women with BRCA1 or BRCA2 mutations." Genetics in Medicine : Official Journal of the American College of Medical Genetics 3.6 (November 2001): 422-425.
PMID
11715007
Source
epmc
Published In
Genetics in Medicine : Official Journal of the American College of Medical Genetics
Volume
3
Issue
6
Publish Date
2001
Start Page
422
End Page
425
DOI
10.1097/00125817-200111000-00008

Disease genes and chromosomes: disease maps of the human genome. Chromosome 9.

Authors
Gilbert, F; Kauff, N
MLA Citation
Gilbert, F, and Kauff, N. "Disease genes and chromosomes: disease maps of the human genome. Chromosome 9." Genetic Testing 5.2 (January 2001): 157-174.
PMID
11551106
Source
epmc
Published In
Genetic Testing
Volume
5
Issue
2
Publish Date
2001
Start Page
157
End Page
174
DOI
10.1089/109065701753145664

SpinThin, a simple, inexpensive technique for preparation of thin-layer cervical cytology from liquid-based specimens

Authors
Khalbuss, WE; Rudomina, D; Kauff, ND; Chuang, L; Melamed, MR
MLA Citation
Khalbuss, WE, Rudomina, D, Kauff, ND, Chuang, L, and Melamed, MR. "SpinThin, a simple, inexpensive technique for preparation of thin-layer cervical cytology from liquid-based specimens." June 25, 2000.
Source
crossref
Published In
Cancer
Volume
90
Issue
3
Publish Date
2000
Start Page
135
End Page
142
DOI
10.1002/1097-0142(20000625)90:3<135::AID-CNCR1>3.0.CO;2-L

SpinThin, a simple, inexpensive technique for preparation of thin-layer cervical cytology from liquid-based specimens: data on 791 cases.

BACKGROUND: Acceptance of liquid-based fixatives for cervical cytology has been limited by the more complex slide-preparation procedures, increased cost, and reports that increased sensitivity has been based largely on comparison with conventional cytology without histologic correlation. Here the authors describe and evaluate a technically simple and relatively inexpensive method (which they call SpinThin) for preparing Cytospin (Shandon Inc., Pittsburgh, PA) cervical cytology slides from samples in liquid fixative using a modified electric toothbrush holder to put the cells in suspension. Results are compared with conventional cytology and histologic biopsy. METHODS: A total of 791 cervical cytology specimens from 2 patient groups at high risk of uterine cervical neoplasia were entered into this study, and a spatula and cytobrush (174 specimens) or cytobroom (617 specimens) were used to collect conventional smears. The collection device with remaining cellular sample was placed in an alcohol-based fixative solution; the cells were put into suspension by a brief burst of vibration using a modified electric toothbrush holder, then cytocentrifuged on a slide and stained with the Papanicolaou technique. RESULTS: Specimen adequacy in SpinThin slides was better than that of conventional cytology smears. However, the prevalence of dysplasia, including atypical squamous cells of undetermined significance (ASCUS-D), in conventional smears and SpinThin slides was the same--27% and 25%, respectively--and excluding ASCUS-D, it was 20% in both. The prevalence of neoplasia (low or high grade squamous intraepithelial lesion, or carcinoma) histologically was 31% in the 647 cases biopsied, and agreement with histology was similar for SpinThin and conventional smears. CONCLUSIONS: Using a simple and relatively inexpensive new technique (Spin-Thin), slides prepared from fluid-based cervical cytology specimens obtained with the cytobrush or cytobroom correlated very well with the corresponding conventional smears within major diagnostic categories, and both correlated well with histology.

Authors
Khalbuss, WE; Rudomina, D; Kauff, ND; Chuang, L; Melamed, MR
MLA Citation
Khalbuss, WE, Rudomina, D, Kauff, ND, Chuang, L, and Melamed, MR. "SpinThin, a simple, inexpensive technique for preparation of thin-layer cervical cytology from liquid-based specimens: data on 791 cases." Cancer 90.3 (June 2000): 135-142.
PMID
10896326
Source
epmc
Published In
Cancer
Volume
90
Issue
3
Publish Date
2000
Start Page
135
End Page
142
DOI
10.1002/1097-0142(20000625)90:3<135::aid-cncr1>3.3.co;2-c

Disease genes and chromosomes: disease maps of the human genome.Chromosome 12.

Authors
Gilbert, F; Kauff, N
MLA Citation
Gilbert, F, and Kauff, N. "Disease genes and chromosomes: disease maps of the human genome.Chromosome 12." Genetic Testing 4.3 (January 2000): 319-333.
PMID
11142767
Source
epmc
Published In
Genetic Testing
Volume
4
Issue
3
Publish Date
2000
Start Page
319
End Page
333
DOI
10.1089/10906570050501588

Trauma in the obstetric patient: Evaluation and management

Authors
Kauff, ND; Tejani, N
MLA Citation
Kauff, ND, and Tejani, N. "Trauma in the obstetric patient: Evaluation and management." Primary Care Update for Ob/Gyns 5.1 (January 1998): 16-20.
Source
crossref
Published In
Primary Care Update for Ob/Gyns
Volume
5
Issue
1
Publish Date
1998
Start Page
16
End Page
20
DOI
10.1016/S1068-607X(97)00117-0

Intractable bleeding managed with Foley catheter tamponade after dilation and evacuation.

Hemorrhage is one of the most frequent complications after dilation and evacuation. A small fraction of patients with hemorrhage will not respond to standard therapies. We discuss a case where both reaspiration and standard pharmacologic therapy failed to control hemorrhage and where hemorrhage was ultimately controlled by tamponade with two Foley catheters. We propose this method as an additional alternative for controlling hemorrhage after dilation and evacuation before resorting to angiographic embolization or surgery.

Authors
Kauff, ND; Chelmow, D; Kawada, CY
MLA Citation
Kauff, ND, Chelmow, D, and Kawada, CY. "Intractable bleeding managed with Foley catheter tamponade after dilation and evacuation." American Journal of Obstetrics and Gynecology 173.3 Pt 1 (September 1995): 957-958.
PMID
7573279
Source
epmc
Published In
American Journal of Obstetrics and Gynecology
Volume
173
Issue
3 Pt 1
Publish Date
1995
Start Page
957
End Page
958
DOI
10.1016/0002-9378(95)90377-1
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