Kouros Owzar

Overview:

cancer pharmacogenomics
drug induced neuropathy, neutropenia and hypertension
statistical genetics
statistical methods for high-dimensional data
copulas
survival analysis
statistical computing

Positions:

Professor of Biostatistics & Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Director, DCI Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

University of North Carolina - Chapel Hill

Grants:

mTOR Therapy in Prostate Cancer: Signatures of Response and Biology of Resistance

Administered By
Institutes and Centers
Awarded By
National Institutes of Health
Role
Statistician
Start Date
End Date

Health Disparity in African Americans: A Meta-analysis of Six Phase III Trials in Metastatic Castration-Resistant Prostate Cancer Men treated with Docetaxel

Administered By
Biostatistics & Bioinformatics
Awarded By
Department of Defense
Role
Collaborator
Start Date
End Date

Profiling the Adenosine Axis in Metastatic Colorectal Cancer

Administered By
Medicine, Medical Oncology
Awarded By
MedImmune, Inc.
Role
Statistician
Start Date
End Date

Computational Resources and Dissemination Core

Administered By
Biostatistics & Bioinformatics
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Pharmacogenomics of Microtubule Targeting Agents

Administered By
Integrative Genomics
Awarded By
University of California, San Francisco
Role
Principal Investigator
Start Date
End Date

Publications:

Comparative analysis of RNA enrichment methods for preparation of Cryptococcus neoformans RNA sequencing libraries.

RNA sequencing (RNA-Seq) experiments focused on gene expression involve removal of ribosomal RNA (rRNA) because it is the major RNA constituent of cells. This process, called RNA enrichment, is done primarily to reduce cost: without rRNA removal, deeper sequencing must be performed to compensate for the sequencing reads wasted on rRNA. The ideal RNA enrichment method removes all rRNA without affecting other RNA in the sample. We tested the performance of three RNA enrichment methods on RNA isolated from Cryptococcus neoformans, a fungal pathogen of humans. We find that the RNase H depletion method is more efficient in depleting rRNA and more specific in recapitulating non-rRNA levels present in unenriched controls than the commonly-used Poly(A) isolation method. The RNase H depletion method is also more effective than the Ribo-Zero depletion method as measured by rRNA depletion efficiency and recapitulation of protein-coding RNA levels present in unenriched controls, while the Ribo-Zero depletion method more closely recapitulates annotated non-coding RNA (ncRNA) levels. Finally, we leverage these data to accurately map the C. neoformans mitochondrial rRNA genes, and also demonstrate that RNA-Seq data generated with the RNase H and Ribo-Zero depletion methods can be used to explore novel C. neoformans long non-coding RNA genes.
Authors
Telzrow, CL; Zwack, PJ; Esher Righi, S; Dietrich, FS; Chan, C; Owzar, K; Alspaugh, JA; Granek, JA
MLA Citation
Telzrow, Calla L., et al. “Comparative analysis of RNA enrichment methods for preparation of Cryptococcus neoformans RNA sequencing libraries.G3 (Bethesda), Aug. 2021. Pubmed, doi:10.1093/g3journal/jkab301.
URI
https://scholars.duke.edu/individual/pub1497146
PMID
34518880
Source
pubmed
Published In
G3 (Bethesda, Md.)
Published Date
DOI
10.1093/g3journal/jkab301

Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma.

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-cell lymphoblastic leukemia/lymphoma. Here we aimed to identify key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/-, and KrasLA1 mice were not observed to harbor significantly higher numbers of nonsynonymous somatic mutations compared with thymic lymphomas from unirradiated p53-/- mice. However, distinct patterns of recurrent mutations arose in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Reporter mice for activation of Notch1 signaling revealed that total-body irradiation (TBI) enriched Notch1hi CD44+ thymocytes that could propagate in vivo after thymocyte transplantation. Mechanistically, genetic inhibition of Notch1 signaling in immature thymocytes prevented formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, these results demonstrate a critical role of activated Notch1 signaling in driving multistep carcinogenesis of thymic lymphoma following TBI in p53 WT mice. SIGNIFICANCE: These findings reveal the mutational landscape and key drivers in murine radiation-induced thymic lymphoma, a classic animal model that has been used to study radiation carcinogenesis for over 70 years.
Authors
Lee, C-L; Brock, KD; Hasapis, S; Zhang, D; Sibley, AB; Qin, X; Gresham, JS; Caraballo, I; Luo, L; Daniel, AR; Hilton, MJ; Owzar, K; Kirsch, DG
MLA Citation
Lee, Chang-Lung, et al. “Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma.Cancer Res, vol. 81, no. 14, July 2021, pp. 3777–90. Pubmed, doi:10.1158/0008-5472.CAN-20-2823.
URI
https://scholars.duke.edu/individual/pub1482957
PMID
34035082
Source
pubmed
Published In
Cancer Res
Volume
81
Published Date
Start Page
3777
End Page
3790
DOI
10.1158/0008-5472.CAN-20-2823

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.
Authors
Patel, JN; Jiang, C; Owzar, K; Mulkey, F; Luzum, JA; Mamon, HJ; Haller, DG; Dragovich, T; Alberts, SR; Bjarnason, G; Willet, CG; Niedzwiecki, D; Enzinger, P; Ratain, MJ; Fuchs, C; McLeod, HL
MLA Citation
Patel, Jai N., et al. “Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).Pharmacogenet Genomics, vol. 31, no. 9, Dec. 2021, pp. 215–20. Pubmed, doi:10.1097/FPC.0000000000000442.
URI
https://scholars.duke.edu/individual/pub1486059
PMID
34149004
Source
pubmed
Published In
Pharmacogenet Genomics
Volume
31
Published Date
Start Page
215
End Page
220
DOI
10.1097/FPC.0000000000000442

Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.

BACKGROUND: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).
Authors
Quintanilha, JCF; Wang, J; Sibley, AB; Jiang, C; Etheridge, AS; Shen, F; Jiang, G; Mulkey, F; Patel, JN; Hertz, DL; Dees, EC; McLeod, HL; Bertagnolli, M; Rugo, H; Kindler, HL; Kelly, WK; Ratain, MJ; Kroetz, DL; Owzar, K; Schneider, BP; Lin, D; Innocenti, F
MLA Citation
Quintanilha, Julia C. F., et al. “Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.Br J Cancer, Oct. 2021. Pubmed, doi:10.1038/s41416-021-01557-w.
URI
https://scholars.duke.edu/individual/pub1498184
PMID
34616010
Source
pubmed
Published In
Br J Cancer
Published Date
DOI
10.1038/s41416-021-01557-w

Genome-wide association studies of survival in 1520 cancer patients treated with bevacizumab-containing regimens.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10-7 , hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33-1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10-5 , HR = 1.51, 95% CI 1.25-1.82) as well as in TCGA (P = 1.39 × 10-4 , HR = 3.09, 95% CI 1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10-5 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.
Authors
Quintanilha, JCF; Wang, J; Sibley, AB; Xu, W; Espin-Garcia, O; Jiang, C; Etheridge, AS; Ratain, MJ; Lenz, H-J; Bertagnolli, M; Kindler, HL; Dickler, MN; Venook, A; Liu, G; Owzar, K; Lin, D; Innocenti, F
MLA Citation
Quintanilha, Julia C. F., et al. “Genome-wide association studies of survival in 1520 cancer patients treated with bevacizumab-containing regimens.Int J Cancer, Sept. 2021. Pubmed, doi:10.1002/ijc.33810.
URI
https://scholars.duke.edu/individual/pub1497314
PMID
34528705
Source
pubmed
Published In
Int J Cancer
Published Date
DOI
10.1002/ijc.33810