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

Tamura, K., Yu, J., Hata, T., Suenaga, M., Shindo, K., Abe, T., MacGregor-Das, A., Borges, M., Wolfgang, C. L., Weiss, M. J., He, J., Canto, M. I., Petersen, G. M., Gallinger, S., Syngal, S., Brand, R. E., Rustgi, A., Olson, S. H., Stoffel, E., Cote, M. L., Zogopoulos, G., Potash, J. B., Goes, F. S., McCombie, R. W., Zandi, P. P., Pirooznia, M., Kramer, M., Parla, J., Eshleman, J. R., Roberts, N. J., Hruban, R. H., Klein, A. P., Goggins, M. (May 2018) Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci U S A, 115 (18). pp. 4767-4772. ISSN 0027-8424

URL: https://www.ncbi.nlm.nih.gov/pubmed/29669919
DOI: 10.1073/pnas.1720588115

Abstract

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

Item Type: Paper
Uncontrolled Keywords: Cpa1 Cpb1 ER stress pancreatic cancer pancreatitis for the licensing of PALB2 as a pancreatic cancer susceptibility gene. S.S. is a consultant to Myriad Genetics, Inc. R.W.M. has participated in Illumina-sponsored meetings over the past 4 y and received travel reimbursement and an honorarium for presenting at these events. Illumina had no role in decisions relating to the study/work to be published, data collection and analysis of data, and the decision to publish. R.W.M. has participated in Pacific Biosciences-sponsored meetings over the past 3 y and received travel reimbursement for presenting at these events. R.W.M. is a founder and shared holder of Orion Genomics, which focuses on plant genomics and cancer genetics. R.W.M. is a scientific advisory board member for RainDance Technologies, Inc. None of the other authors has any conflicts of interest to declare.
Subjects: organs, tissues, organelles, cell types and functions > organelles, types and functions > endoplasmic reticulum
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > McCombie lab
Depositing User: Matt Covey
Date: 1 May 2018
Date Deposited: 21 May 2018 16:41
Last Modified: 21 May 2018 16:41
PMCID: PMC5939087
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36578

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