Mutations in the pancreatic secretory enzymes and are associated with pancreatic cancer.

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (, , , and ) in a hospital series of pancreatic cancer cases and controls. Variants in , (encoding carboxypeptidase B1 and A1), and were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, = 0.027). Among familial pancreatic cancer cases, ER stress-inducing variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls ( = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls ( < 0.01). More ER stress-inducing variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing or variant, compared with 1 of 2,068 controls ( < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in and are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.