Abstract 2324: Replication and genetic risk score analysis for pancreatic cancer in a diverse multiethnic population

Background: Pancreatic cancer is one of the most fatal cancers, and it is projected to be the second leading cause of cancer-related death by 2030. Genome-wide association studies (GWAS) conducted in populations of European, Japanese, and Chinese-ancestry have identified several single nucleotide polymorphisms (SNPs) associated with pancreatic cancer risk. No studies yet have attempted to replicate these SNPs in African Americans, Latinos, or Native Hawaiians. In this study, we aimed to replicate the associations of 31 GWAS-identified SNPs with pancreatic cancer and build and test a polygenic risk score (PRS) for pancreatic cancer in an ethnically diverse population. Methods: We evaluated 31 risk variants in a nested case control study within the Multiethnic Cohort (MEC) and the Southern Community Cohort Study (SCCS). We included 692 pancreatic ductal adenocarcinoma (PDAC) cases and 13,777 controls from African-American (230 cases/5,235 controls), white (132 cases/570 controls), Japanese-American (182 cases/3,284 controls), Latino (105 cases/ 2,935 controls), and Native Hawaiian (43 cases/1,753 controls) participants. We first tested the association between each SNP and PDAC in a combined sample and by race/ethnicity. We then established a PRS using the 31 SNPs and log-odds weights from the combined sample results and tested the association between the score and PDAC risk. Results: Eleven of the 31 SNPs were replicated in the combined sample, ten initially discovered in GWAS of European ancestry and one in Japanese ancestry. Of these 11, three were also replicated in African Americans, two in whites, one in Japanese Americans, and one in Latinos at p 0.05 in the multiethnic sample. The PRS showed strong performance in the multiethnic sample, with the top quintile (80%-100%) for the risk score associated with an odds ratio of 2.27 (95% CI: 1.73, 2.99) for PDAC compared with the middle quintile. Notably, the PRS was associated with PDAC risk within each racial/ethnic group (OR for continuous PRS ranged from 1.27 in Native Hawaiians to 1.97 in African Americans; P heterogeneity=0.16). Conclusion: This is the first study to test GWAS-identified risk variants associated with pancreatic cancer in a multiethnic population including high-risk African Americans, Japanese Americans and Latinos. We successfully replicated 11 of the 31 risk variants in the combined sample. PRS performance was high in majority of racial/ethnic groups. Our results suggest a potential utility of PRS with GWAS-identified risk variants for the identification of individuals at increased risk for PDAC across multiple ethnic groups. Citation Format: David Bogumil, David Conti, Xin Sheng, Lucy Xia, Xiao-ou Shu, Stephen Pandol, William Blot, Wei Zheng, Loic Le Marchand, Christopher Haiman, Veronica Wendy Setiawan. Replication and genetic risk score analysis for pancreatic cancer in a diverse multiethnic population [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2324.