Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Deleterious variants in CPA1 and CPB1 associated with pancreatic cancer risk may not always progress through a clinical syndrome of pancreatitis.
“Deleterious variants in CPA1 and CPB1 associated with pancreatic cancer risk may not always progress through a clinical syndrome of pancreatitis.”
Cites
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0155 · Cited by 7,094 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress
Lee, A. S. (2005) · Methods · doi:10.1016/j.ymeth.2004.10.010 · Cited by 994 · see citing works
Hereditary Pancreatitis and the Risk of Pancreatic Cancer
Lowenfels, A. B., Maisonneuve, P., DiMagno, E. P., Elitsur, Y., Gates, L. K., Perrault, J., Whitcomb, D. C., & International Hereditary Pancreatitis Study Group (1997) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/89.6.442 · Cited by 988 · see citing works
Exomic Sequencing Identifies <i>PALB2</i> as a Pancreatic Cancer Susceptibility Gene
Jones, S., Hruban, R. H., Kamiyama, M., Borges, M., Zhang, X., Parsons, D. W., Lin, J. C.-H., Palmisano, E., Brune, K., Jaffee, E. M., et al. (2009) · Science · doi:10.1126/science.1171202 · Cited by 826 · see citing works
Self-citationCanto, M. I., Harinck, F., Hruban, R. H., Offerhaus, G. J., Poley, J.-W., Kamel, I., Nio, Y., Schulick, R. S., Bassi, C., Kluijt, I., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-303108 · Cited by 784 · see citing works
Self-citationGoggins, M., Overbeek, K. A., Brand, R., Syngal, S., Del Chiaro, M., Bartsch, D. K., Bassi, C., Carrato, A., Farrell, J., Fishman, E. K., et al. (2020) · Gut · doi:10.1136/gutjnl-2019-319352 · Cited by 659 · see citing works
Self-citationGermline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.
Goggins, M., Schutte, M. E. M., Lü, J., Moskaluk, C. A., Weinstein, C. L., Petersen, G. M., Yeo, C. J., Jackson, C. E., Lynch, H. T., Hruban, R. H., et al. (1996) · PubMed · Cited by 642 · see citing works
Self-citationThe rules and impact of nonsense-mediated mRNA decay in human cancers
Lindeboom, R. G. H., Supek, F., & Lehner, B. (2016) · Nature Genetics · doi:10.1038/ng.3664 · Cited by 549 · see citing works
Risk of Pancreatic Cancer in Families With Lynch Syndrome
Kastrinos, F. (2009) · JAMA · doi:10.1001/jama.2009.1529 · Cited by 544 · see citing works
Mechanism and regulation of the nonsense-mediated decay pathway
Hug, N., Longman, D., & Cáceres, J. F. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw010 · Cited by 535 · see citing works
<i>ATM</i> Mutations in Patients with Hereditary Pancreatic Cancer
Roberts, N. J., Jiao, Y., Yu, J., Kopelovich, L., Petersen, G. M., Bondy, M. L., Gallinger, S., Schwartz, A. G., Syngal, S., Cote, M. L., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0194 · Cited by 491 · see citing works
Self-citationDeleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma
Shindo, K., Yu, J., Suenaga, M., Fesharakizadeh, S., Cho, C., Macgregor-Das, A., Siddiqui, A., Witmer, P. D., Tamura, K., Song, T. J., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.72.3502 · Cited by 458 · see citing works
Self-citationRosendahl, J., Witt, H., Szmola, R., Bhatia, E., Ózsvári, B., Landt, O., Schulz, H.-U., Gress, T. M., Pfützer, R., Löhr, M., et al. (2008) · Nature Genetics · doi:10.1038/ng.2007.44 · Cited by 439 · see citing works
Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction
Ræder, H., Johansson, S., Holm, P. I., Haldorsen, I. S., Mas, E., Sbarra, V., Nermoen, I., Eide, S. Å., Grevle, L., Bjørkhaug, L., et al. (2005) · Nature Genetics · doi:10.1038/ng1708 · Cited by 377 · see citing works
Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
Roberts, N. J., Norris, A. L., Petersen, G. M., Bondy, M. L., Brand, R., Gallinger, S., Kurtz, R. C., Olson, S. H., Rustgi, A. K., Schwartz, A. G., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0402 · Cited by 361 · see citing works
Self-citation(2006) · PubMed · Cited by 347 · see citing works
Vasen, H., Ibrahim, I., Ponce, C. G., Slater, E. P., Matthäi, E., Carrato, A., Earl, J., Robbers, K., van Mil, A. M., Potjer, T., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.64.0730 · Cited by 344 · see citing works
Effect of predicted protein-truncating genetic variants on the human transcriptome
Rivas, M. A., Pirinen, M., Conrad, D. F., Lek, M., Tsang, E. K., Karczewski, K. J., Maller, J. B., Kukurba, K. R., DeLuca, D. S., Fromer, M., et al. (2015) · Science · doi:10.1126/science.1261877 · Cited by 313 · see citing works
Genetic Risk Factors for Pancreatic Disorders
Whitcomb, D. C. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.01.069 · Cited by 305 · see citing works
Variants in CPA1 are strongly associated with early onset chronic pancreatitis
Witt, H., Beer, S., Rosendahl, J., Chen, J.-M., Chandak, G. R., Masamune, A., Bence, M., Szmola, R., Oracz, G., Macek, M., et al. (2013) · Nature Genetics · doi:10.1038/ng.2730 · Cited by 305 · see citing works
Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic Cancer
Grant, R. C., Selander, I., Connor, A. A., Selvarajah, S., Borgida, A., Briollais, L., Petersen, G. M., Lerner-Ellis, J., Holter, S., & Gallinger, S. (2015) · Gastroenterology · doi:10.1053/j.gastro.2014.11.042 · Cited by 299 · see citing works
Self-citationChilds, E. J., Mocci, E., Campa, D., Bracci, P. M., Gallinger, S., Goggins, M., Li, D., Neale, R. Ε., Olson, S. H., Scélo, G., et al. (2015) · Nature Genetics · doi:10.1038/ng.3341 · Cited by 265 · see citing works
Self-citationFjeld, K., Weiß, F. U., Lasher, D., Rosendahl, J., Chen, J., Johansson, B. B., Kirsten, H., Ruffert, C., Masson, E., Steine, S. J., et al. (2015) · Nature Genetics · doi:10.1038/ng.3249 · Cited by 184 · see citing works
Yu, J., Sadakari, Y., Shindo, K., Suenaga, M., Brant, A., Almario, J. A. N., Borges, M., Barkley, T., Fesharakizadeh, S., Ford, M., et al. (2017) · Gut · doi:10.1136/gutjnl-2015-311166 · Cited by 164 · see citing works
Self-citationAdaptive Unfolded Protein Response Attenuates Alcohol-Induced Pancreatic Damage
Lugea, A., Tischler, D., Nguyen, J., Gong, J., Gukovsky, I., French, S. W., Gorelick, F. S., & Pandol, S. J. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.11.038 · Cited by 159 · see citing works
Kereszturi, É., Szmola, R., Kukor, Z., Simon, P., Weiß, F. U., Lerch, M. M., & Sahin‐Tóth, M. (2009) · Human Mutation · doi:10.1002/humu.20853 · Cited by 156 · see citing works
Chaffee, K. G., Oberg, A. L., McWilliams, R. R., Majithia, N., Allen, B. A., Kidd, J., Singh, N., Hartman, A.-R., Wenstrup, R. J., & Petersen, G. M. (2018) · Genetics in Medicine · doi:10.1038/gim.2017.85 · Cited by 144 · see citing works
Self-citationThe role of protein synthesis and digestive enzymes in acinar cell injury
Logsdon, C. D., & Ji, B. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.36 · Cited by 129 · see citing works
Malats, N., Casals, T., Porta, M. S., et al. (2001) · Gut · doi:10.1136/gut.48.1.70 · Cited by 125 · see citing works
Beer, S., Zhou, J., Szabó, A., Keiles, S. B., Chandak, G. R., Witt, H., & Sahin‐Tóth, M. (2012) · Gut · doi:10.1136/gutjnl-2012-303090 · Cited by 111 · see citing works
Genetic risk in chronic pancreatitis: the misfolding-dependent pathway
Sahin‐Tóth, M. (2017) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000380 · Cited by 109 · see citing works
Abe, T., Blackford, A. L., Tamura, K., Ford, M., McCormick, P., Chuidian, M., Almario, J. A., Borges, M., Lennon, A. M., Shin, E. J., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01512 · Cited by 102 · see citing works
Self-citationNo Association Between CEL–HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations
Zou, W., Boulling, A., Masamune, A., Issarapu, P., Masson, E., Wu, H., Sun, X.-T., Hu, L., Zhou, D., He, L., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.071 · Cited by 72 · see citing works
Zhou, Y., Chen, L., Zhang, Y., Hu, S., Dong, Z., Wu, M. J., Chen, Q., Zhuang, Z., & Du, X. (2019) · Molecular Medicine · doi:10.1186/s10020-019-0113-2 · Cited by 69 · see citing works
Polymorphisms of SPINK1 N34S and CFTR in Patients with Sporadic and Familial Pancreatic Cancer
Matsubayashi, H., & Fukushima, N. (2003) · Cancer Biology & Therapy · doi:10.4161/cbt.2.6.530 · Cited by 68 · see citing works
Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis
Lasher, D., Szabó, A., Masamune, A., Chen, J., Xiao, X. K., Whitcomb, D. C., Barmada, M. M., Ewers, M., Ruffert, C., Paliwal, S., et al. (2019) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000051 · Cited by 65 · see citing works
Xiao, X. K., Jones, G., Sevilla, W. A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.734384 · Cited by 60 · see citing works
Allelic imbalance of somatic mutations in cancer genomes and transcriptomes
Rhee, J., Lee, S., Park, W., Kim, Y.-H., & Kim, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-01966-z · Cited by 47 · see citing works
CFTR, SPINK1, PRSS1, and CTRC Mutations Are Not Associated With Pancreatic Cancer in German Patients
Schubert, S., Traub, F., Brakensiek, K., von Kopylow, K., Marohn, B., Mälzer, M., Gaedcke, J., Kreipe, H. H., & Stuhrmann, M. (2014) · Pancreas · doi:10.1097/mpa.0000000000000166 · Cited by 42 · see citing works
Dalva, M., Jellas, K. E., Steine, S. J., et al. (2016) · Pancreatology · doi:10.1016/j.pan.2016.10.006 · Cited by 39 · see citing works
Yamamoto, K., Pousette, Å., Chow, P., et al. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)45919-4 · Cited by 37 · see citing works
Pancreatic Exocrine Dysfunction in Maturity-Onset Diabetes of the Young Type 3
Vesterhus, M. N., Ræder, H., Johansson, S. E., et al. (2008) · Diabetes Care · doi:10.2337/dc07-1002 · Cited by 34 · see citing works
PRSS1 mutation: a possible pathomechanism of pancreatic carcinogenesis and pancreatic cancer
Liu, Q., Guo, L. T., Zhang, S., Wang, J., Lin, X., & Gao, F. (2019) · Molecular Medicine · doi:10.1186/s10020-019-0111-4 · Cited by 33 · see citing works
Wu, H., Zhou, D., Berki, D. M., Geisz, A., Zou, W., Sun, X., Hu, L., Zhao, Z., Zhao, A., He, L., et al. (2017) · Human Mutation · doi:10.1002/humu.23254 · Cited by 25 · see citing works
A Hybrid Likelihood Model for Sequence-Based Disease Association Studies
Chen, Y.-C., Carter, H. K., Parla, J. S., Kramer, M., Goes, F. S., Pirooznia, M., Zandi, P. P., McCombie, W. R., Potash, J. B., & Karchin, R. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003224 · Cited by 24 · see citing works
Self-citationVariants in pancreatic carboxypeptidase genesCPA2andCPB1are not associated with chronic pancreatitis
Nakano, E., Geisz, A., Masamune, A., et al. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00241.2015 · Cited by 23 · see citing works
Novel Assay for Pancreatic Cellular Damage
Pousette, Å., Fernstad, R., Sköldefors, H., et al. (1988) · Pancreas · doi:10.1097/00006676-198808000-00009 · Cited by 15 · see citing works
Lack of association between the pancreatitis risk allele CEL-HYB and pancreatic cancer
Shindo, K., Yu, J., Suenaga, M., Fesharakizadeh, S., Tamura, K., Almario, J. A., Brant, A., Borges, M. W., Siddiqui, A., Datta, L. W., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15137 · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Goggins, M., Overbeek, K. A., Brand, R., Syngal, S., Del Chiaro, M., Bartsch, D. K., Bassi, C., Carrato, A., Farrell, J., Fishman, E. K., et al. (2020) · Gut · doi:10.1136/gutjnl-2019-319352 · Cited by 659 · see citing works
Self-citationThe pancreatic cancer genome revisited
Hayashi, A., Hong, J., & Iacobuzio-Donahue, C. A. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00463-z · Cited by 211 · see citing works
Abe, T., Blackford, A. L., Tamura, K., Ford, M., McCormick, P., Chuidian, M., Almario, J. A., Borges, M., Lennon, A. M., Shin, E. J., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01512 · Cited by 102 · see citing works
Self-citationGenetics of familial and sporadic pancreatic cancer
Wood, L. D., Yurgelun, M. B., & Goggins, M. G. (2019) · Gastroenterology · doi:10.1053/j.gastro.2018.12.039 · Cited by 91 · see citing works
Self-citation
- Authors
- 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.
- Affiliations
- Johns Hopkins University (US)
- Mayo Clinic (US)
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
- Dana-Farber Cancer Institute (US)
- University of Pittsburgh (US)
- Abramson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Michigan (US)
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201;
- Research Institute of the McGill University Health Centre (CA)
- Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
- Cold Spring Harbor Laboratory (US)
- ORCID
- Tamura, Koji
- Yu, Jun
- Hata, Tatsuo
- Shindo, Koji
- Abe, Toshiya
- MacGregor-Das, Anne
- Wolfgang, Christopher L.
- Weiss, Matthew J.
- He, Jin
- Canto, Marcia Irene
- Petersen, Gloria M.
- Syngal, Sapna
- Brand, Randall E.
- Rustgi, Anil
- Olson, Sara H.
- Stoffel, Elena
- Zogopoulos, George
- Potash, James B.
- Goes, Fernando S.
- Zandi, Peter P.
- Pirooznia, Mehdi
- Kramer, Melissa
- Eshleman, James R.
- Roberts, Nicholas J.
- Hruban, Ralph H.
- Goggins, Michael
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-04-18
- Volume
- 115
- Issue
- 18
- Pages
- 4767-4772
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5939087
- OpenAlex
- W2801812177
- Cited by
- 95
- References
- 49
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 12 · 2023: 11 · 2022: 17 · 2021: 15 · 2020: 6 · 2019: 12 · 2018: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (CA62924, CA176828, CA210170, CA154823, CA132829, CA190889, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- pancreatic cancer, CPA1, germline mutations, endoplasmic reticulum stress, pancreatic acinar cells, hereditary cancer predisposition, protein misfolding, enzyme secretion
- MeSH terms
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Proteins, Pancreatic Neoplasms, Genetic Predisposition to Disease, Carboxypeptidases A, Carboxypeptidase B, Cell Line, Tumor, Endoplasmic Reticulum Stress
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
