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

Koji Tamura, Jun Yu, Tatsuo Hata, Masaya Suenaga, Koji Shindo, Toshiya Abe, Anne MacGregor-Das, Michael Borges, Christopher Wolfgang, Matthew J Weiss, Jin He, Marcia Canto, Gloria M. Petersen, Steven Gallinger, Sapna Syngal, Randall E. Brand, Anil Rustgi, Sara H. Olson, Elena Stoffel, Michele L. CoteGeorge Zogopoulos, James Bennett Potash, Fernando S Goes, Richard W. McCombie, Peter P Zandi, Mehdi Pirooznia, Melissa Kramer, Jennifer Parla, James Eshleman, Nicholas Roberts, Ralph H Hruban, Alison Klein, Michael S Goggins

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4767-4772
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number18
DOIs
StatePublished - May 1 2018

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Carboxypeptidases A
Pancreatic Neoplasms
Endoplasmic Reticulum Stress
Mutation
Enzymes
Genes
Acinar Cells
HEK293 Cells
Pancreatitis
Odds Ratio

Keywords

  • CPA1
  • CPB1
  • ER stress
  • Pancreatic cancer
  • Pancreatitis

ASJC Scopus subject areas

  • General

Cite this

Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. / Tamura, Koji; Yu, Jun; Hata, Tatsuo; Suenaga, Masaya; Shindo, Koji; Abe, Toshiya; MacGregor-Das, Anne; Borges, Michael; Wolfgang, Christopher; Weiss, Matthew J; He, Jin; Canto, Marcia; Petersen, Gloria M.; Gallinger, Steven; Syngal, Sapna; Brand, Randall E.; Rustgi, Anil; Olson, Sara H.; Stoffel, Elena; Cote, Michele L.; Zogopoulos, George; Potash, James Bennett; Goes, Fernando S; McCombie, Richard W.; Zandi, Peter P; Pirooznia, Mehdi; Kramer, Melissa; Parla, Jennifer; Eshleman, James; Roberts, Nicholas; Hruban, Ralph H; Klein, Alison; Goggins, Michael S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 18, 01.05.2018, p. 4767-4772.

Research output: Contribution to journalArticle

Tamura, K, Yu, J, Hata, T, Suenaga, M, Shindo, K, Abe, T, MacGregor-Das, A, Borges, M, Wolfgang, C, Weiss, MJ, He, J, Canto, M, Petersen, GM, Gallinger, S, Syngal, S, Brand, RE, Rustgi, A, Olson, SH, Stoffel, E, Cote, ML, Zogopoulos, G, Potash, JB, Goes, FS, McCombie, RW, Zandi, PP, Pirooznia, M, Kramer, M, Parla, J, Eshleman, J, Roberts, N, Hruban, RH, Klein, A & Goggins, MS 2018, 'Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 18, pp. 4767-4772. https://doi.org/10.1073/pnas.1720588115
Tamura, Koji ; Yu, Jun ; Hata, Tatsuo ; Suenaga, Masaya ; Shindo, Koji ; Abe, Toshiya ; MacGregor-Das, Anne ; Borges, Michael ; Wolfgang, Christopher ; Weiss, Matthew J ; He, Jin ; Canto, Marcia ; Petersen, Gloria M. ; Gallinger, Steven ; Syngal, Sapna ; Brand, Randall E. ; Rustgi, Anil ; Olson, Sara H. ; Stoffel, Elena ; Cote, Michele L. ; Zogopoulos, George ; Potash, James Bennett ; Goes, Fernando S ; McCombie, Richard W. ; Zandi, Peter P ; Pirooznia, Mehdi ; Kramer, Melissa ; Parla, Jennifer ; Eshleman, James ; Roberts, Nicholas ; Hruban, Ralph H ; Klein, Alison ; Goggins, Michael S. / Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 18. pp. 4767-4772.
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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.",
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AU - Tamura, Koji

AU - Yu, Jun

AU - Hata, Tatsuo

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AU - Shindo, Koji

AU - Abe, Toshiya

AU - MacGregor-Das, Anne

AU - Borges, Michael

AU - Wolfgang, Christopher

AU - Weiss, Matthew J

AU - He, Jin

AU - Canto, Marcia

AU - Petersen, Gloria M.

AU - Gallinger, Steven

AU - Syngal, Sapna

AU - Brand, Randall E.

AU - Rustgi, Anil

AU - Olson, Sara H.

AU - Stoffel, Elena

AU - Cote, Michele L.

AU - Zogopoulos, George

AU - Potash, James Bennett

AU - Goes, Fernando S

AU - McCombie, Richard W.

AU - Zandi, Peter P

AU - Pirooznia, Mehdi

AU - Kramer, Melissa

AU - Parla, Jennifer

AU - Eshleman, James

AU - Roberts, Nicholas

AU - Hruban, Ralph H

AU - Klein, Alison

AU - Goggins, Michael S

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