Epidemiologic studies have consistently found Jews to be at increased risk of pancreatic cancer compared to non-Jewish whites. This excess risk is not accounted for by BRCA1/2 mutations or by other known risk factors. We therefore propose to examine in Jewish subjects the most significant single nucleotide polymorphism (SNP) associations observed in the Pancreatic Cancer Cohort and Case-Control Consortium (PanScan) genome-wide association study (GWAS), to perform an exploratory GWAS to identify additional SNPs associated with pancreatic cancer in the Jewish population, and to assess genetic underpinning of the relationship between Jewish ancestry and pancreatic cancer. To do this, we will use GWAS data from PanScan and from the Johns Hopkins University study titled "Validation and Fine-Scale Mapping of Pancreatic Cancer Susceptibility Loci." In our study, Jewish subjects with be identified with a panel of genetic markers that correlate strongly with self-reported Jewish ancestry. Preliminary sample size calculations, based upon participants in the PanScan and Johns Hopkins University studies, give an estimate of around 500 Jewish cases and 300 unaffected Jewish controls. We will use the program Eigensoft (v.3.0) to conduct a principal component analysis that will genetically identify Jewish subjects among other racial/ethnic groups. We will validate these genetically identified Jews by using a subset of self-reported Jewish subjects in the Yale University, Johns Hopkins, and Memorial Sloan Kettering studies, all sub-studies in the PanScan and Johns Hopkins University studies. We will perform the SNP replication analysis, conduct the GWAS, and will assess genetic contribution using the program PLINK (v.1, 07): whole genome association analysis toolset. Logistic regression models will be used for each SNP, with pancreatic cancer as the outcome variable and each SNP as a predictor variable. Any association with P-value less than 0.05 will be considered significant for the candidate gene approach, and less than 10-6 for the GWAS approach. This will be the first study to determine a genetic basis, distinct from BRCA1/2 mutations, for the excess risk of pancreatic cancer in Jews. Results from this work will open paths to identify genetic interactions and will begin to approach the possibility of genetic screening for pancreatic cancer in the Jewish population.

Public Health Relevance

Jews have repeatedly been found to be at increased risk of pancreatic cancer. However, this increased risk has not been adequately explained. We will validate previously identified significant variants and perform a genome-wide association study limited to Jewish individuals to find genetic variants associated with pancreatic cancer in this high-risk population.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F16-L (20))
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Schmidt, Michael K
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Yale University
Public Health & Prev Medicine
Schools of Medicine
New Haven
United States
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Streicher, Samantha A; Yu, Herbert; Lu, Lingeng et al. (2014) Case-control study of aspirin use and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 23:1254-63