Journal
GYNECOLOGIC ONCOLOGY
Volume 161, Issue 2, Pages 545-552Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2021.02.028
Keywords
Ovarian cancer; Extreme of ages; Molecular profiles; BRCA1; 2; Homologous recombination DNA; repair deficiency; PARP inhibitor
Categories
Funding
- National Institutes of Health/National Cancer Institute [K12 CA184746]
- Breast Cancer Research Foundation
- Cycle for Survival
- Department of Defense Ovarian Cancer Research Academy [OC150111]
- Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute [P30 CA008748]
- Weickart Ovarian Cancer Postdoctoral Fellowship
- Stand Up to Cancer
- Ovarian Cancer Research Foundation Liz Tilberis Award
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Younger HGSOC patients more frequently carry pathogenic BRCA1 germline mutations and genomic features of HRD, while older patients preferentially display aging-related mutational signatures, fewer pathogenic BRCA1 germline mutations and genomic features of HRD.
Objectives. To determine if the mutational landscapes and genomic features of homologous recombination DNA repair defects (HRD) vary between younger and older patients with high-grade serous ovarian cancer (HGSOC). Methods. Younger and older women were defined as bottom and top age quartiles, respectively. HGSOCs from 15 younger (median 49 years, range 35-53) and 15 older women (median 72 years, range 70-87) were subjected to whole-exome sequencing (WES). For validation, HGSOC WES data were obtained from The Cancer Genome Atlas (TCGA), including 38 younger (median 45 years, range 34-50) and 30 older women (median 74 years, range 68-84). Mutational profiles, BRCA1/2 status, genomic HRD features, and for TCGA cases RNA-sequencing-based HRD transcriptomic signatures were assessed. Results. In the institutional cohort, pathogenic germline BRCA1/2 mutations were more frequent in younger (5/15) than older women (0/15, p = 0.042). No somatic BRCA1/2 mutations were identified. HGSOCs from older patients preferentially displayed aging-related mutational signatures and, in contrast to younger patients, harbored CCNE1 amplifications (3/15, 20%). In the TCGA cohort, pathogenic germline BRCA1 (younger 8/38, older 0/30, p = 0.007) but not BRCA2 mutations (young 3/38, older 4/30, p = 0.691) were more frequent in younger patients. Again, no somatic BRCA1/2 mutations were identified. HGSOCs from younger women more frequently displayed genomic features of HRD (all, p < 0.05), a significant HRD gene-signature enrichment, but less fre-quently CCNE1 amplification (p = 0.05). Immunoreactive CLOVAR subtypes were more common in HGSOCs from younger women, and proliferative subtypes in HGSOCs from older women (p = 0.041). Conclusions. HGSOC patients diagnosed at an older age less frequently harbor pathogenic BRCA1 germline mutations and genomic features of HRD than younger women. Individualized treatment options, particularly pertaining to use of PARP inhibitors, in older women may be warranted. (c) 2021 Elsevier Inc. All rights reserved.
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