Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance
Open accessAbstract
PURPOSE: To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS: Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS: Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION: The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.
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The risk of PDAC increases with the number of affected first-degree relatives with pancreatic cancer and in those who carry a pathogenic germline variant in a pancreatic cancer susceptibility gene.
“The risk increases with the number of affected first-degree relatives with pancreatic cancer and in those who carry a pathogenic germline variant in a pancreatic cancer susceptibility gene.9-11”
From The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival (2022) · cites this paper as [9]
The PDAC risk in the familial group appears significant enough to warrant surveillance.
“This observation is consistent with previous reports that the PDAC risk in the familial group appears significant enough to warrant surveillance.9,10,14”
From The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival (2022) · cites this paper as [9]
Germline testing should be considered for individuals eligible for pancreatic cancer surveillance.
“Therefore, germline testing should be considered for individuals eligible for pancreatic cancer surveillance.”
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- Authors
- Abe, T., Blackford, A. L., Tamura, K., Ford, M., McCormick, P., Chuidian, M., Almario, J. A., Borges, M., Lennon, A. M., Shin, E. J., Klein, A. P., Hruban, R. H., Canto, M. I., & Goggins, M.
- Affiliations
- Johns Hopkins University (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-01
- Volume
- 37
- Issue
- 13
- Pages
- 1070-1080
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC6494358
- OpenAlex
- W2920864397
- Cited by
- 102
- References
- 31
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 14 · 2023: 23 · 2022: 14 · 2021: 23 · 2020: 10 · 2019: 5 · 2018: 1
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50CA062924, R01CA176828)
- 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
- germline mutations, pancreatic cancer surveillance, tumor progression, ATM, BRCA2, BRCA1, PALB2, TP53, CPA1, genetic testing, hereditary cancer
- MeSH terms
- Fanconi Anemia Complementation Group N Protein, Aged, Female, Humans, Male, Medical History Taking, Middle Aged, Pancreatic Neoplasms, Risk Factors, Tumor Suppressor Protein p53, Germ-Line Mutation, Disease Progression, BRCA1 Protein, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, BRCA2 Protein, Early Detection of Cancer, Ataxia Telangiectasia Mutated Proteins
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