Identification of common variants in BRCA2 and MAP2K4 for susceptibility to sporadic pancreatic cancer.

Germline mutations in genes that cause hereditary syndromes are highly predisposed to familial pancreatic cancer. However, genetic susceptibility to sporadic pancreatic cancer is largely uncovered. We conducted a two-stage association study on pancreatic cancer that included 981 cases and 1991 controls in the first stage followed by a second stage (2603 cases and 2877 controls). Using an approach based on candidate genes whose roles in pancreatic cancer have been well known, we identified two new susceptibility loci. rs11571836 located in the BRCA2 3-untranslated region was significantly associated with lower expression of BRCA2 transcript and increased pancreatic cancer risk [odds ratio 1.30, 95% confidence interval 1.141.47, P 7.64 10(5)] in a recessive manner. rs12939944 located in the MAP2K4 intron was associated with decreased risk (odds ratio 0.82, 95% confidence interval 0.740.91, P 0.0001) in a dominant manner. Our results demonstrate for the first time that common variants in BRCA2 and MAP2K4 are susceptibility to sporadic pancreatic cancer.