Abstract 1326: A pooled genome-wide association study of pancreatic cancer susceptibility loci in American Jews

Abstract

Abstract Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews. The higher risk of pancreatic cancer in Jews can be partially explained by the increased frequency of BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population; however, the remaining 40-70% excess risk of pancreatic cancer in Jews is not explained by other established non-genetic and genetic risk factors. The genetic origins of modern Ashkenazi Jews can be traced back to a founder population bottleneck between the 11th and 15th centuries follow by a rapid endogamous population expansion, making the Ashkenazi Jewish population a genetic isolate ideal for exploring genetic contributions to pancreatic cancer. We conducted a genome-wide association study (GWAS) in a case-control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2,332 controls, identified in the database of Genotypes and Phenotypes (dbGaP) Pancreatic Cancer Cohort and Case-Control Consortium I/II (PanScan I/II), Pancreatic Cancer Case-Control Consortium (PanC4), and Genetic Epidemiology Research on Adult Health and Aging (GERA) data sets. We then examined those single nucleotide polymorphisms (SNPs) with P<10-7 in an expanded sample set, of 539 full- plus part-Jewish pancreatic cancer patients and 4,117 full- plus part-Jewish controls from the same data sets. Jewish ancestry was genetically determined using seeded fast principal component analysis. In our data set, the part-Jewish subjects had mixed genetic ancestry both from Jews and from non-Jewish white-Europeans. Among the full Jews, a novel genome-wide significant association was detected on chromosome 19p12 (rs66562280, OR=1.55, 95% CI=1.33-1.81, P=2.30x10-8). A suggestive association was detected on chromosome 19p13.3 (rs2656937, OR=1.53, 95% CI=1.31-1.78, P=9.96x10-8). Similar associations were seen for these SNPs among the full- plus part-Jews. No SNPs meeting the quality control filter inclusion criteria were found in the full- plus part-Jewish subjects to be significant at the P=10-7 level. Overall, we identified in Jews one novel susceptibility locus and one suggestive novel susceptibility locus for pancreatic cancer that warrant follow-up work. This is the first GWAS conducted for pancreatic cancer in the increased-risk Jewish population. The novel susceptibility locus discovered on chromosome 19p12 could explain up to ~15%, and the novel suggestive susceptibility locus on chromosome 19p13.3 could explain up to an additional ~15% of the increased risk for pancreatic cancer in the Jewish population. Citation Format: Samantha A. Streicher, Alison P. Klein, Sara H. Olson, Robert C. Kurtz, Andrew T. DeWan, Hongyu Zhao, Harvey A. Risch. A pooled genome-wide association study of pancreatic cancer susceptibility loci in American Jews [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1326. doi:10.1158/1538-7445.AM2017-1326