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

作者：Koji Tamura, Jun Yu, Tatsuo Hata, Masaya Suenaga, Koji Shindo, Toshiya Abe, Anne M. Macgregor-Das, Michael W. Borges, Christopher Lee Wolfgang, Matthew John Weiss, Jin Peng He, Marcia Irene Canto, Gloria M. Petersen, Steven Gallinger, Sapna Syngal, Randall E. Brand, Anil K. Rustgi, Sara H. Olson, Elena Martinez Stoffel, Michele L. Coté, George Zogopoulos, James B. Potash, Fernando S. Goes, William Richard McCombie, Peter P. Zandi, Mehdi Pirooznia, Melissa Kramer, Jennifer S. Parla, James R. Eshleman, Nicholas Jason Roberts, Ralph H. Hruban, Alison Patricia Klein, Michael Goggins · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · DOI：10.1073/pnas.1720588115 · 被引用次数：96 · 研究领域：Pancreatic and Hepatic Oncology Research、Pancreatitis Pathology and Treatment、Pancreatic function and diabetes

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.