Germline mutation in DNA-repair genes is associated with poor survival in BRCA1/2-negative breast cancer patients
- PMID: 31432574
- PMCID: PMC7938415
- DOI: 10.1111/cas.14175
Germline mutation in DNA-repair genes is associated with poor survival in BRCA1/2-negative breast cancer patients
Abstract
BRCA1/2 genes are the most frequently germline mutated DNA-repair genes, and the survival of BRCA1/2 carriers has been extensively explored in breast cancer. However, the prevalence of germline mutations in non-BRCA1/2 DNA-repair genes and the survival of carriers are largely unknown in a large cohort of unselected breast cancer patients. Germline mutations in 16 DNA-repair genes were determined using a multigene panel in 7657 BRCA1/2-negative breast cancer patients who were unselected for family history of cancer or age at diagnosis. Among the 7657 BRCA1/2-negative breast cancer patients, 257 (3.4%) carried at least 1 pathogenic germline mutation in the 16 DNA-repair genes. The prevalence of DNA-repair gene mutations was significantly higher in familial breast cancers (5.2%, P = 0.002) and early-onset breast cancers (diagnosed at and before the age of 40) (4.5%, P = 0.003) than that of sporadic breast cancers (2.9%) (diagnosed above age of 40), respectively. The DNA-repair gene mutation carriers were significantly more likely to have a larger tumor (P = 0.04) and axillary lymph node metastasis (P = 0.03). Moreover, DNA-repair gene mutation was an independent unfavorable factor for recurrence-free survival (adjusted hazard ratio [HR] = 1.38, 95% CI: 1.00-1.91, P = 0.05) and disease-specific survival (adjusted HR=1.63, 95% CI: 1.04-2.57, P = 0.03) in this cohort. Overall, 3.4% of BRCA1/2-negative breast cancer patients carried germline mutations in the 16 DNA-repair genes, and the DNA-repair gene mutation carriers exhibited an aggressive phenotype and had poor survival compared with noncarriers.
Keywords: DNA-repair genes; breast cancer; cancer susceptibility genes; germline mutations; survival.
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Figures
Similar articles
-
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. doi: 10.1158/1078-0432.CCR-16-3227. Epub 2017 Jul 19. Clin Cancer Res. 2017. PMID: 28724667
-
Patterns of recurrence and metastasis in BRCA1/BRCA2-associated breast cancers.Cancer. 2020 Jan 15;126(2):271-280. doi: 10.1002/cncr.32540. Epub 2019 Oct 3. Cancer. 2020. PMID: 31581314 Free PMC article.
-
RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients.Int J Cancer. 2018 Oct 15;143(8):1935-1942. doi: 10.1002/ijc.31579. Epub 2018 Jul 26. Int J Cancer. 2018. PMID: 29726012
-
BRCA gene structure and function in tumor suppression: a repair-centric perspective.Cancer J. 2010 Jan-Feb;16(1):39-47. doi: 10.1097/PPO.0b013e3181cf0204. Cancer J. 2010. PMID: 20164689 Review.
-
How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility?DNA Repair (Amst). 2019 Sep;81:102668. doi: 10.1016/j.dnarep.2019.102668. Epub 2019 Jul 8. DNA Repair (Amst). 2019. PMID: 31337537 Free PMC article. Review.
Cited by
-
Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study.Genes (Basel). 2022 Dec 29;14(1):106. doi: 10.3390/genes14010106. Genes (Basel). 2022. PMID: 36672847 Free PMC article.
-
Mortality after second malignancy in breast cancer survivors compared to a first primary cancer: a nationwide longitudinal cohort study.NPJ Breast Cancer. 2022 Jul 14;8(1):82. doi: 10.1038/s41523-022-00447-5. NPJ Breast Cancer. 2022. PMID: 35835760 Free PMC article.
-
Multiple cancer susceptible genes sequencing in BRCA-negative breast cancer with high hereditary risk.Ann Transl Med. 2020 Nov;8(21):1417. doi: 10.21037/atm-20-2999. Ann Transl Med. 2020. PMID: 33313162 Free PMC article.
-
Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers.J Clin Med. 2020 Sep 17;9(9):3003. doi: 10.3390/jcm9093003. J Clin Med. 2020. PMID: 32957588 Free PMC article.
References
-
- Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer. 2016;16:35‐42. - PubMed
-
- Nielsen FC, van Overeem Hansen T, Sorensen CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer. 2016;16:599‐612. - PubMed
-
- Castro E, Romero‐Laorden N, Del Pozo A, et al. PROREPAIR‐B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration‐resistant prostate cancer. J Clin Oncol. 2019;37:490‐503. - PubMed
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous