Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma
Open accessAbstract
Purpose: Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods: To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results: Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion: Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.
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Classic medical history features (young age at PDAC diagnosis and family history of pancreatic or other cancers) have poor sensitivity in identifying individuals at high genomic risk for pancreatic cancer.
“However, these classic features have poor sensitivity in identifying individuals at high genomic risk for pancreatic cancer.182–185”
From Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review (2021) · cites this paper as [182]
The Discussion (p. 6) says most mutation carriers with pancreatic cancer do not meet family-history criteria for gene testing, supporting the claim about poor sensitivity of family history. The Results (p. 1) report that carriers were younger on average, but the paper does not establish that young age at PDAC diagnosis has poor sensitivity for identifying them. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGenomic risk contributes to up to 8% of PDAC cases.
“Recent studies estimate that genomic risk contributes to up to 8% of PDAC cases,180–184”
From Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review (2021) · cites this paper as [182]
The Results (p. 1) report deleterious germline mutations in 3.9% of 854 patients with pancreatic cancer, supporting a genetic contribution in some cases. This paper does not estimate that contribution at 8%; its reported estimate is lower, so it supports the general point but not the cited upper figure. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDeleterious variants have been reported in about 5-10% of patients with apparently sporadic pancreatic cancer.
“Deleterious variants have also been reported in ~5–10% of patients with apparently sporadic pancreatic cancer.”
Mutation carriers who develop pancreatic cancer are diagnosed at a slightly younger age, about 3-5 years, than those with sporadic forms of the disease.
“mutation carriers who develop pancreatic cancer are diagnosed at a slightly younger age (~3–5 years) than those with sporadic forms of the disease.”
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Cites
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377 · see citing works
Self-citationExomic 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 · cited 1× · see citing works
“1 , 51 81 (9) 79 (23) 51-60 199 (23) 80 (24) 61-70 297 (35) 95 (28) 71-80 220 (26) 69 (20) $ 80 57 (7) 16 (5) Sex Male 455 (53) 181 (53) Female 399 (47) 158 (47) Race White 756 (89) 280 (83) African American 52 (6) 31 (9) Other 46 (5) 28 (8) Family history of pancreatic cancer 109 (12.”
Self-citationFrequent detection of pancreatic lesions in asymptomatic high-risk individuals
Canto, M. I., Hruban, R. H., Fishman, E. K., Kamel, I. R., Schulick, R., Zhang, Z., Topazian, M., Takahashi, N., Fletcher, J., Petersen, G., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.01.005 · Cited by 648 · see citing works
Self-citation<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-citationBRCA2 germline mutations in familial pancreatic carcinoma
Hahn, S. A., Greenhalf, B., Ellis, I., Sina-Frey, M., Rieder, H., Korte, B., Gerdes, B., Kress, R., Ziegler, A., Raeburn, J. A., et al. (2003) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/95.3.214 · Cited by 480 · see citing works
Holter, S., Borgida, A., Dodd, A., Grant, R., Semotiuk, K., Hedley, D., Dhani, N., Narod, S., Akbari, M., Moore, M., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.7401 · Cited by 398 · 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-citationVasen, 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
PALB2 mutations in European familial pancreatic cancer families
Slater, E., Langer, P., Niemczyk, E., Strauch, K., Butler, J., Habbe, N., Neoptolemos, J., Greenhalf, W., & Bartsch, D. (2010) · Clinical Genetics · doi:10.1111/j.1399-0004.2010.01425.x · Cited by 278 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
State-of-the-art strategies for targeting the DNA damage response in cancer
Pilié, P. G., Tang, C., Mills, G. B., & Yap, T. A. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0114-z · Cited by 1,189 · see citing works
Molecular subtypes of pancreatic cancer
Collisson, E. A., Bailey, P., Chang, D. K., & Biankin, A. V. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0109-y · Cited by 892 · see citing works
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-citationHu, C., Hart, S. N., Polley, E. C., Gnanaolivu, R., Shimelis, H., Lee, K. Y., Lilyquist, J., Na, J., Moore, R., Antwi, S. O., et al. (2018) · JAMA · doi:10.1001/jama.2018.6228 · Cited by 577 · see citing works
Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., Raghavan, S., Kim, J., Brais, L. K., Ragon, D., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0275 · Cited by 367 · see citing works
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms
Lowery, M. A., Wong, W., Jordan, E. J., Lee, J. W., Kemel, Y., Vijai, J., Mandelker, D., Zehir, A., Capanu, M., Salo-Mullen, E., et al. (2018) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djy024 · Cited by 224 · see citing works
Yurgelun, M. B., Chittenden, A. B., Morales-Oyarvide, V., Rubinson, D. A., Dunne, R. F., Kozak, M. M., Qian, Z. R., Welch, M. W., Brais, L. K., Da Silva, A., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-018-0009-5 · Cited by 217 · see citing works
The 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
Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review
Kenner, B., Chari, S. T., Kelsen, D., Klimstra, D. S., Pandol, S. J., Rosenthal, M., Rustgi, A. K., Taylor, J. A., Yala, A., Abul-Husn, N., et al. (2021) · Pancreas · doi:10.1097/mpa.0000000000001762 · Cited by 158 · see citing works
Why is pancreatic cancer so deadly? The pathologist's view
Hruban, R. H., Gaida, M. M., Thompson, E., Hong, S., Noë, M., Brosens, L. A., Jongepier, M., Offerhaus, G. J. A., & Wood, L. D. (2019) · The Journal of Pathology · doi:10.1002/path.5260 · Cited by 115 · see citing works
Self-citationAbe, 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-citationTamura, K., Yu, J., Hata, T., Suenaga, M., Shindo, K., Abe, T., MacGregor-Das, A., Borges, M., Wolfgang, C. L., Weiss, M. J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720588115 · Cited by 95 · 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-citationRisk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the <i>ATM</i> Gene
Hsu, F.-C., Roberts, N. J., Childs, E., Porter, N., Rabe, K. G., Borgida, A., Ukaegbu, C., Goggins, M. G., Hruban, R. H., Zogopoulos, G., et al. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.3701 · Cited by 91 · see citing works
Self-citationTargeting DNA damage repair pathways in pancreas cancer
Crowley, F., Park, W., & O’Reilly, E. M. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09983-1 · Cited by 43 · see citing works
Bannon, S. A., Montiel, M. F., Goldstein, J. B., Dong, W., Mork, M. E., Borras, E., Hasanov, M., Varadhachary, G. R., Maitra, A., Katz, M. H., et al. (2018) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-18-0014 · Cited by 40 · see citing works
Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models
Saiki, Y., Jiang, C., Ohmuraya, M., & Furukawa, T. (2021) · Cancers · doi:10.3390/cancers14010071 · Cited by 38 · see citing works
Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers
Alhusaini, A., Cannon, A., Maher, S. G., Reynolds, J. V., & Lynam-Lennon, N. (2021) · Biomedicines · doi:10.3390/biomedicines9081024 · Cited by 24 · see citing works
- Authors
- Shindo, K., Yu, J., Suenaga, M., Fesharakizadeh, S., Cho, C., Macgregor-Das, A., Siddiqui, A., Witmer, P. D., Tamura, K., Song, T. J., Navarro Almario, J. A., Brant, A., Borges, M., Ford, M., Barkley, T., He, J., Weiss, M. J., Wolfgang, C. L., Roberts, N. J., Hruban, R. H., Klein, A. P., & Goggins, M.
- Affiliations
- Johns Hopkins University (US)
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2017-10-20
- Volume
- 35
- Issue
- 30
- Pages
- 3382-3390
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5648172
- OpenAlex
- W2741937391
- Cited by
- 458
- References
- 9
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 60 · 2023: 74 · 2022: 61 · 2021: 78 · 2020: 44 · 2019: 49 · 2018: 41 · 2017: 9
- FWCI
- 17.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K99CA190889, R00CA190889, P50CA062924, R01CA176828, U01CA210170)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- pancreatic ductal adenocarcinoma, germline mutations, sporadic pancreatic cancer, BRCA2, ATM, BRCA1, PALB2, MLH1, CDKN2A, TP53, BUB1B, Bub3, family history (medicine), genetic testing, hereditary cancer, periampullary neoplasms
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Gene Frequency, Humans, Male, Middle Aged, Pancreatic Neoplasms, United States, Prevalence, Sequence Analysis, DNA, Germ-Line Mutation, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal
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