Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer
Open accessAbstract
Purpose Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.Methods Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.Results We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05).Conclusion Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.
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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 [185]
10% of patients with PDAC harbor germline pathogenic variants.
“and that 10% of patients with PDAC harbor germline pathogenic variants.185”
From Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review (2021) · cites this paper as [185]
The comparison of outcomes between screen-detected PDAC and PDAC diagnosed after dropping out of surveillance is worthwhile because these groups have similar demographic/risk characteristics, but the number of such cases was small.
“Comparing outcomes of those diagnosed with a screen-detected PDAC to those whose PDAC was diagnosed after dropping out of surveillance is worthwhile because these groups have similar demographic/risk characteristics, and for whom data on pancreatic cancer outcomes is limited,41-43 but the number of such cases was small.”
From The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival (2022) · cites this paper as [43]
Deleterious 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.”
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- Authors
- 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., Bui, J. L., Yuan, C., Li, T., Li, W., Masuda, A., Gu, M., Bullock, A. J., Chang, D. T., Clancy, T. E., Linehan, D. C., Findeis-Hosey, J. J., Doyle, L. A., Thorner, A. R., Ducar, M. D., Wollison, B. M., Khalaf, N., Perez, K., Syngal, S., Aguirre, A. J., Hahn, W. C., Meyerson, M. L., Fuchs, C. S., Ogino, S., Hornick, J. L., Hezel, A. F., Koong, A. C., Nowak, J. A., & Wolpin, B. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Rochester Medicine (US)
- Stanford Cancer Institute (US)
- Dana-Farber Cancer Institute (US)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Yurgelun, Matthew B.
- ORCID
- Yurgelun, Matthew B.
- Chittenden, Anu B.
- Rubinson, Douglas A.
- Dunne, Richard F.
- Kozak, Margaret M.
- Qian, Zhi Rong
- Brais, Lauren K.
- Bui, Justin L.
- Yuan, Chen
- Li, Tingting
- Li, Wanwan
- Masuda, Atsuhiro
- Gu, Mancang
- Bullock, Andrea J.
- Chang, Daniel T.
- Clancy, Thomas E.
- Linehan, David C.
- Findeis-Hosey, Jennifer J.
- Doyle, Leona A.
- Thorner, Aaron R.
- Ducar, Matthew D.
- Wollison, Bruce M.
- Khalaf, Natalia
- Perez, Kimberly
- Syngal, Sapna
- Aguirre, Andrew J.
- Hahn, William C.
- Fuchs, Charles S.
- Ogino, Shuji
- Hornick, Jason L.
- Hezel, Aram F.
- Koong, Albert C.
- Nowak, Jonathan A.
- Wolpin, Brian M.
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 21
- Issue
- 1
- Pages
- 213-223
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC6666401
- OpenAlex
- W2810883871
- Cited by
- 217
- References
- 38
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 19 · 2023: 28 · 2022: 36 · 2021: 47 · 2020: 31 · 2019: 19 · 2018: 5 · 2017: 1
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA127003, R01CA124908, R35CA197735, R01CA132829, K08CA218420, U01CA210171)
- 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, Lynch syndrome, BRCA1, BRCA2, overall survival, resected pancreatic cancer, CDKN2A, TP53, APC, PARP inhibitors, platinum-based chemotherapy
- MeSH terms
- Adenocarcinoma, Adult, Aged, Ethnicity, Female, Humans, Male, Middle Aged, Neoplasm Proteins, Pancreatic Neoplasms, Germ-Line Mutation, Disease-Free Survival, Genetic Predisposition to Disease, DNA Breaks, Double-Stranded, High-Throughput Nucleotide Sequencing
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