Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk.
Abstract
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 [PIK3C3 rs76692125 G>A: odds ratio (OR)=1.26, 95% confidence interval (CI)=1.12-1.43 and P=2.07×10-4, INSR rs11668724 G>A: OR=0.89, 95% CI=0.84-0.94 and P=4.21×10-5 and MAP3K4 rs13207108 C>T: OR=0.83, 95% CI=0.75-0.92, P=2.26×10-4]. The combined analysis of these three SNPs exhibited an increased PanC risk in a dose-response manner as the number of unfavorable genotypes increased (P trend<0.0001). The risk-associated rs76692125 A allele was correlated with decreased PIK3C3 mRNA expression levels, while the protective-associated rs11668724 A allele was correlated with increased INSR 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.
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Scholars@Duke
Sheng Luo
Kyle Walsh
Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to neurologic and physical decline, applying these approaches to studying the shared neurobiology of cognition, glial senescence, and gliomagenesis. The lab has a long history studying telomere maintenance in pre-malignant cells and its role in the development of cancer, most notably glioblastoma.
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