Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer

• DOI: 10.1073/pnas.1720588115
• Publication Date: 2018-04-19T15:15:22Z
• Authors: Koji Tamura; Jun Yu; Tatsuo Hata; Masaya Suenaga; Koji Shindo; Toshiya Abe; Anne MacGregor-Das; Michael Borges; Christopher L. Wo...; Matthew J. Weiss; Jin He; Marcia Irene Canto; Gloria M. Petersen; Steven Gallinger; Sapna Syngal; Randall E. Brand; Anil Rustgi; Sara H. Olson; Elena Stoffel; Michele L. Cote; George Zogopoulos; James B. Potash; Fernando S. Goes; Richard W. McCombie; Peter P. Zandi; Mehdi Pirooznia; Melissa Kramer; Jennifer Parla; James R. Eshleman; Nicholas J. Roberts; Ralph H. Hruban; Alison Patricia K...; Michael Goggins
• Keywords: Aged, 80 and over; Male; 0303 health sciences; Carboxypeptidases A; Middle Aged; Endoplasmic Reticulum Stress; Carboxypeptidase B; Neoplasm Proteins; 3. Good health; Pancreatic Neoplasms; 03 medical and health sciences; Cell Line, Tumor; Mutation; Humans; Female; Genetic Predisposition to Disease; Aged

Significance

Much of the inherited susceptibility to pancreatic cancer remains unexplained. Germline variants that cause protein misfolding and impaired secretion of pancreatic enzymes such as CPA1 (encoding carboxypeptidase A1) can cause pancreatic acinar cell endoplasmic reticulum (ER) stress. We investigated the hypothesis that pancreatic cancer could arise from germline variants in genes encoding pancreatic secretory enzymes that induce pancreatic acinar cell stress. We find ∼1% of 1,579 patients with pancreatic cancer vs. 1 of 2,012 controls have germline variants in the genes encoding CPA1 and CPB1 (carboxypeptidase B1) that impair secretion of its protein product and induce ER stress. These findings implicate pancreatic acinar cell stress as a mechanism of pancreatic cancer susceptibility.