Mutations in the pancreatic secretory enzymes <i>CPA1</i> and <i>CPB1</i> are associated with pancreatic cancer

Abstract

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of <i>CPB1</i> and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (<i>PRSS1</i>, <i>CPA1</i>, <i>CTRC</i>, and <i>SPINK1</i>) in a hospital series of pancreatic cancer cases and controls. Variants in <i>CPB1</i>, <i>CPA1</i> (encoding carboxypeptidase B1 and A1), and <i>CTRC</i> were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious <i>CPB1</i> 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, <i>P</i> = 0.027). Among familial pancreatic cancer cases, ER stress-inducing <i>CPB1</i> variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (<i>P</i> = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (<i>P</i> < 0.01). More ER stress-inducing <i>CPA1</i> 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; <i>P</i> = 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 <i>CPA1</i> or <i>CPB1</i> variant, compared with 1 of 2,068 controls (<i>P</i> < 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 <i>CPB1</i> and <i>CPA1</i> are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.