Genome-wide pathway analysis in pancreatic cancer

Purpose: The purpose of this study was to identify candidate single-nucleotide polymorphisms (SNPs) that might play a role in susceptibility to pancreatic cancer, elucidate their potential mechanisms, and generate SNP-to-gene-to-pathway hypotheses. Methods: A genome-wide association study (GWAS) data-set of pancreatic cancer that included 496, 959 SNPs from 3,851 pancreatic cancer patients and 3,934 control subjects of European descent was used in this study. The Identify candidate Causal SNPs and Pathways (ICSNPathway) method was applied to the GWAS dataset. Results: ICSNPathway analysis identified 18 candidate SNPs, 11 genes (including HNF1A and HNF4G), and 30 pathways, which revealed 11 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was one wherein rs2230739 alters the role of ADCY9 in various pathways and processes, including cyclase activity, phosphorus oxygen lyase activity, hsa04912, hsa04540, hsa04020, and hsa00230 (0.010 ≤p< 0.001; 0.038 ≤ false discovery rate (FDR) ≤ 0.016). The second strongest mechanism was that rs16859886 modulates ADCY10 to affect its role in pathways including cyclase activity, phosphorus oxygen lyase activity, nucleobase, nucleoside, and nucleotide metabolic processing, and hsa00230 (0.010≤p < 0.001;0.038≤FDR ≤ 0.016). Conclusions: By using the ICSNPathway to analyze pancreatic cancer GWAS data, 18 candidate SNPs, 11 genes (including ADCY9, ADCY10, HNF1A, and HNF4G), and 30 pathways were identified that might contribute to the susceptibility of patients to pancreatic cancer.