Associations of novel variants in , and of the ATM pathway genes with pancreatic cancer risk.

The ATM serine/threonine kinase (ATM) pathway plays important roles in pancreatic cancer (PanC) development and progression, but the roles of genetic variants of the genes in this pathway in the etiology of PanC are unknown. In the present study, we assessed associations between 31,499 single nucleotide polymorphisms (SNPs) in 198 ATM pathway-related genes and PanC risk using genotyping data from two previously published PanC genome-wide association studies (GWASs) of 15,423 subjects of European ancestry. In multivariable logistic regression analysis, we identified three novel independent SNPs to be significantly associated with PanC risk [ rs76692125 G>A: odds ratio (OR)=1.26, 95% confidence interval (CI)=1.12-1.43 and =2.07×10, rs11668724 G>A: OR=0.89, 95% CI=0.84-0.94 and =4.21×10 and rs13207108 C>T: OR=0.83, 95% CI=0.75-0.92, =2.26×10]. The combined analysis of these three SNPs exhibited an increased PanC risk in a dose-response manner as the number of unfavorable genotypes increased ( <0.0001). The risk-associated rs76692125 A allele was correlated with decreased mRNA expression levels, while the protective-associated rs11668724 A allele was correlated with increased mRNA expression levels, but additional mechanistic studies of these SNPs are warranted. Once validated, these SNPs may serve as biomarkers for PanC risk in populations of European ancestry.