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

作者：Tamura Koji; Yu Jun; Hata Tatsuo; Suenaga Masaya; Shindo Koji; Abe Toshiya; MacGregor Das Anne; Borges Michael; Wolfgang Christopher L; Weiss Matthew J; He Jin; Canto Marcia Irene; Petersen Gloria M; Gallinger Steven; Syngel Sapna; Brand Randall E; Rustgi Anil; Olson Sara H; Stoffel Elena; Cote Michele L; Zogopoulos George; Potash James B; Goes Fernando S; McCombie Richard W; Zandi Peter P; Pirooznia Mehdi; Kramer Melissa; Parla Jennifer t

来源：Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(18): 4767-4772.

DOI：10.1073/pnas.1720588115

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

• 出版日期2018-5-1