Clinical Trial

. 2018 May 1;115(18):4767-4772.

doi: 10.1073/pnas.1720588115. Epub 2018 Apr 18.

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

Koji Tamura¹, Jun Yu^{1

2}, Tatsuo Hata¹, Masaya Suenaga¹, Koji Shindo¹, Toshiya Abe¹, Anne MacGregor-Das¹, Michael Borges¹, Christopher L Wolfgang^{1

2

3

4}, Matthew J Weiss^{2

4}, Jin He^{2

4}, Marcia Irene Canto^{4

5}, Gloria M Petersen⁶, Steven Gallinger⁷, Sapna Syngal⁸, Randall E Brand⁹, Anil Rustgi^{10

11

12

13}, Sara H Olson¹⁴, Elena Stoffel¹⁵, Michele L Cote¹⁶, George Zogopoulos^{17

18}, James B Potash¹⁹, Fernando S Goes¹⁹, Richard W McCombie²⁰, Peter P Zandi¹⁹, Mehdi Pirooznia¹⁹, Melissa Kramer²⁰, Jennifer Parla^{20

21}, James R Eshleman^{1

3

4}, Nicholas J Roberts^{1

4}, Ralph H Hruban^{1

3

4}, Alison Patricia Klein^{1

3

4

22}, Michael Goggins^{23

3

4

5}

Affiliations

¹ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
² Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
³ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
⁴ The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
⁵ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
⁶ Health Sciences Research, Mayo Clinic, Rochester, MN 55905.
⁷ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
⁸ Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215.
⁹ Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
¹⁰ Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹¹ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹² Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹³ Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017.
¹⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
¹⁶ Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201.
¹⁷ The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9.
¹⁸ The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
¹⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
²⁰ Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
²¹ InGenious Targeting Laboratory, Ronkonkoma, NY 11779.
²² Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
²³ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu.

PMID: 29669919
PMCID: PMC5939087
DOI: 10.1073/pnas.1720588115

Clinical Trial

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

Koji Tamura et al. Proc Natl Acad Sci U S A. 2018.

. 2018 May 1;115(18):4767-4772.

doi: 10.1073/pnas.1720588115. Epub 2018 Apr 18.

Authors

Affiliations

¹ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
² Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
³ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
⁴ The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
⁵ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
⁶ Health Sciences Research, Mayo Clinic, Rochester, MN 55905.
⁷ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
⁸ Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215.
⁹ Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
¹⁰ Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹¹ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹² Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹³ Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
¹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017.
¹⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
¹⁶ Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201.
¹⁷ The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9.
¹⁸ The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
¹⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
²⁰ Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
²¹ InGenious Targeting Laboratory, Ronkonkoma, NY 11779.
²² Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
²³ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu.

PMID: 29669919
PMCID: PMC5939087
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.

Keywords: CPA1; CPB1; ER stress; pancreatic cancer; pancreatitis.

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Conflict of interest statement

Conflict of interest statement: M.G., A.P.K., and R.H.H. have received royalties 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.

Figures

**Fig. 1.**
Secretion, enzymatic activity, and ER stress of *CPB1* variants. (A and D) Secreted proCpb1 protein by SDS/PAGE and Coomassie Blue staining. (B) Cpb1 secretion (black bars) and enzymatic activity (gray bars) relative to wild-type *CPB1* levels (average ± SE, n = 3). (C, *Top*) Expression of BiP in cells transfected with *CPB1* wild type, and truncating and nonstop deleterious variants lacking secretion (p.*418W, p.E23*, p.Q130*, p.Q187*). (C and E, *Bottom*) Relative BiP/actin protein expression quantified by densitometry (average ± SE, n = 3 independent transfections). (C, *Top*) Expression of the ER stress protein BiP (Grp78) in cells transfected with wild-type *CPB1*, deleterious variants lacking secretion (p.N120del, p.G146R, p.A366P), and a benign variant (p.L403V). **P < 0.01–0.02; ^variant transcript predicted to undergo NMD in vivo.

See this image and copyright information in PMC

References

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1. Vasen H, et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: Outcome of long-term prospective follow-up studies from three European expert centers. J Clin Oncol. 2016;34:2010–2019. - PubMed
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Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous