Kyle Walsh

Overview:

Dr. Walsh’s research program focuses on genetic and epigenetic factors contributing to cancer predisposition in children and adults, with a special interest in brain tumors. This research is informed by both epidemiology and anthropological genetics, with computational work stressing statistical methodologies for “gene hunting” (e.g. GWAS, fine-mapping, admixture mapping, whole-genome sequencing). The laboratory engages in functional genomics research, investigating the biological impact of genetic variants linked to cancer risk, with a particular focus on regulation of telomere maintenance in pre-malignant cells. 

Positions:

Associate Professor of Neurosurgery

Neurosurgery
School of Medicine

Associate Professor in Population Health Sciences

Population Health Sciences
School of Medicine

Associate Professor in Pediatrics

Pediatrics, Children's Health Discovery Institute
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2011

Yale University School of Medicine

Grants:

My Childhood Cancer: Survey Series

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to Pediatric Glioma in Individuals and Diverse populations

Administered By
Neurosurgery
Awarded By
University of Southern California
Role
Principal Investigator
Start Date
End Date

The role of rare and common variants in genetic predisposition to medulloblastoma

Administered By
Neurosurgery
Awarded By
Sontag Foundation
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to pediatric Osteosarcoma and Interaction with Measures of Childhood Growth

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development

Administered By
Pediatrics, Children's Health Discovery Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population.

Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition to longer leukocyte telomere length (LTL) and osteosarcoma risk in this independent multi-ethnic dataset. In our sample, we were unable to replicate previously-reported loci for osteosarcoma risk or metastasis detected in GWAS of European-ancestry individuals in either ethnicity-stratified analyses or meta-analysis across ethnic groups. Our analyses did confirm that genetic predisposition to longer LTL is a risk factor for osteosarcoma (ORmeta: 1.22; 95% CI: 1.09-1.36; P = 3.8 × 10-4), and the strongest effect was seen in Hispanic subjects (OR: 1.32; 95% CI: 1.12-1.54, P = 6.2 × 10-4). Our findings shed light on the replicability of osteosarcoma risk loci across ethnicities and motivate further characterization of these genetic factors in diverse clinical cohorts.
Authors
Zhang, C; Hansen, HM; Semmes, EC; Gonzalez-Maya, J; Morimoto, L; Wei, Q; Eward, WC; DeWitt, SB; Hurst, JH; Metayer, C; de Smith, AJ; Wiemels, JL; Walsh, KM
MLA Citation
Zhang, Chenan, et al. “Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population..” Bone, vol. 130, Jan. 2020. Pubmed, doi:10.1016/j.bone.2019.115070.
URI
https://scholars.duke.edu/individual/pub1411824
PMID
31525475
Source
pubmed
Published In
Bone
Volume
130
Published Date
Start Page
115070
DOI
10.1016/j.bone.2019.115070

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.
Authors
Brown, AL; de Smith, AJ; Gant, VU; Yang, W; Scheurer, ME; Walsh, KM; Chernus, JM; Kallsen, NA; Peyton, SA; Davies, GE; Ehli, EA; Winick, N; Heerema, NA; Carroll, AJ; Borowitz, MJ; Wood, BL; Carroll, WL; Raetz, EA; Feingold, E; Devidas, M; Barcellos, LF; Hansen, HM; Morimoto, L; Kang, AY; Smirnov, I; Healy, J; Laverdière, C; Sinnett, D; Taub, JW; Birch, JM; Thompson, P; Spector, LG; Pombo-de-Oliveira, MS; DeWan, AT; Mullighan, CG; Hunger, SP; Pui, C-H; Loh, ML; Zwick, ME; Metayer, C; Ma, X; Mueller, BA; Sherman, SL; Wiemels, JL; Relling, MV; Yang, JJ; Lupo, PJ; Rabin, KR
MLA Citation
Brown, Austin L., et al. “Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome..” Blood, vol. 134, no. 15, Oct. 2019, pp. 1227–37. Pubmed, doi:10.1182/blood.2018890764.
URI
https://scholars.duke.edu/individual/pub1402523
PMID
31350265
Source
pubmed
Published In
Blood
Volume
134
Published Date
Start Page
1227
End Page
1237
DOI
10.1182/blood.2018890764

Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome.

Authors
de Smith, AJ; Walsh, KM; Morimoto, LM; Francis, SS; Hansen, HM; Jeon, S; Gonseth, S; Chen, M; Sun, H; Luna-Fineman, S; Antillón, F; Girón, V; Kang, AY; Smirnov, I; Shao, X; Whitehead, TP; Barcellos, LF; Jolly, KW; Healy, J; Laverdière, C; Sinnett, D; Taub, JW; Birch, JM; Thompson, PD; Pombo-de-Oliveira, MS; Spector, LG; DeWan, AT; Mueller, BA; Chiang, C; Metayer, C; Ma, X; Wiemels, JL
MLA Citation
de Smith, Adam J., et al. “Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome..” Leukemia, vol. 33, no. 11, Nov. 2019, pp. 2746–51. Pubmed, doi:10.1038/s41375-019-0514-9.
URI
https://scholars.duke.edu/individual/pub1397340
PMID
31296947
Source
pubmed
Published In
Leukemia
Volume
33
Published Date
Start Page
2746
End Page
2751
DOI
10.1038/s41375-019-0514-9

Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.

The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r2  > 0.9) withRPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression.
Authors
Xu, X; Qian, D; Liu, H; Cruz, D; Luo, S; Walsh, KM; Abbruzzese, JL; Zhang, X; Wei, Q
MLA Citation
Xu, Xinyuan, et al. “Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk..” Mol Carcinog, vol. 58, no. 8, Aug. 2019, pp. 1338–48. Pubmed, doi:10.1002/mc.23018.
URI
https://scholars.duke.edu/individual/pub1381281
PMID
30997723
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
58
Published Date
Start Page
1338
End Page
1348
DOI
10.1002/mc.23018

Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma.

Although genome-wide association studies have identified several susceptibility loci for adult glioma, little is known regarding the potential contribution of genetic variation in the human leukocyte antigen (HLA) region to glioma risk. HLA associations have been reported for various malignancies, with many studies investigating selected candidate HLA polymorphisms. However, no systematic analysis has been conducted in glioma patients, and no investigation into potential non-additive effects has been described. We conducted comprehensive genetic analyses of HLA variants among 1746 adult glioma patients and 2312 controls of European-ancestry from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, and we imputed HLA alleles using a reference panel of 5225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the HLA region are linked, we created multigene haplotypes consisting of the genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, inclusion of a dominance term significantly improved the model for multigene haplotype HLA-DRB1*1501-DQA1*0102-DQB1*0602 (P = 0.002). Heterozygous carriers of the haplotype had an increased risk of glioma [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.01-1.49], while homozygous carriers were at decreased risk compared with non-carriers (OR 0.64; 95% CI 0.40-1.01). Our results suggest that the DRB1*1501-DQA1*0102-DQB1*0602 haplotype may contribute to the risk of glioma in a non-additive manner, with the positive dominance effect partly explained by an epistatic interaction with HLA-DRB1*0401-DQA1*0301-DQB1*0301.
Authors
Zhang, C; de Smith, AJ; Smirnov, IV; Wiencke, JK; Wiemels, JL; Witte, JS; Walsh, KM
MLA Citation
Zhang, Chenan, et al. “Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma..” J Neurooncol, vol. 135, no. 2, Nov. 2017, pp. 237–44. Pubmed, doi:10.1007/s11060-017-2569-7.
URI
https://scholars.duke.edu/individual/pub1266206
PMID
28721485
Source
pubmed
Published In
J Neurooncol
Volume
135
Published Date
Start Page
237
End Page
244
DOI
10.1007/s11060-017-2569-7