The Contribution of Genetic Modifiers to Ovarian Cancer Risk in BRCA1 and BRCA2 Pathogenic Variant Carriers

The article presents the current state of knowledge on genetic modifiers of ovarian cancer risk in women carrying pathogenic variants (PVs) in the BRCA1 and BRCA2 genes, which are major contributors to hereditary susceptibility to this malignancy. Although PV carriers have high disease penetrance (BRCA1: ~40% and BRCA2: 11-27%), substantial variability in individual risk is observed, suggesting the influence of additional genetic variants. Background: Ovarian cancer is characterized by late detection and high mortality, and a significant portion of risk among BRCA1/2 carriers is shaped by reproductive and environmental factors as well as genetic modifiers. The article emphasizes that carriers of the same BRCA PV can exhibit markedly different risk levels depending on additional variants that modulate key biological processes, such as DNA repair, cell cycle regulation, and apoptosis. Methods: A systematic literature search covering the years 1996-2025 was conducted in the PubMed database. Initially, 734 publications were identified; after removing duplicates, thematically irrelevant articles, non-full-text papers, and studies not meeting the inclusion criteria, 47 articles were included in the review. These studies covered candidate gene analyses, GWAS, and data from the CIMBA consortium, which enables the examination of large cohorts of PV carriers. Results: The review identified numerous variants associated with increased or decreased ovarian cancer risk in BRCA1 carriers, including the following: OGG1, DR4, MDM2, CYP2A7, CASP8, ITGB3, HRAS1, TRIM61, and MTHFR. The reviewed studies also identified both protective and risk-increasing variants among BRCA2 PV carriers: UNG, TDG, and PARP2, and haplotypes in ATM, BRIP1, BARD1, MRE11, RAD51, and 9p22.2. The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP. Protective variants include BNC2 and LINC00824. The only SNP reaching genome-wide significance (p < 5 × 10^-8) was in BNC2. Conclusions: The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets.