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

## TL;DR

This review explores how additional genetic factors influence ovarian cancer risk in women with BRCA1 or BRCA2 mutations, aiming to improve personalized risk prediction and treatment strategies.

## Contribution

The paper systematically reviews and summarizes the current evidence on genetic modifiers affecting ovarian cancer risk in BRCA1/2 carriers.

## Key findings

- Multiple genetic variants were identified that modify ovarian cancer risk in BRCA1/2 carriers, influencing DNA repair and cell cycle pathways.
- Some variants, like BNC2, show genome-wide significance in reducing ovarian cancer risk for both BRCA1 and BRCA2 carriers.
- The findings suggest that genetic modifiers can improve personalized risk assessment and inform prevention strategies for BRCA1/2 carriers.

## Abstract

Women who carry pathogenic variants in the BRCA1 or BRCA2 genes have a high risk of developing ovarian cancer, but this risk varies greatly between individuals. This variability cannot be explained by BRCA1/2 variants alone and suggests that other genetic factors play an important role. This review summarizes current evidence on additional genetic variants, known as genetic modifiers, which can increase or decrease ovarian cancer risk in BRCA1/2 carriers. Based on a systematic review of studies published between 1996 and 2025, including candidate gene studies and large genome-wide association analyses, multiple risk-modifying variants were identified for BRCA1 carriers, BRCA2 carriers, and both. Most of these variants influence biological pathways involved in DNA repair, cell cycle control, and apoptosis. Understanding how these genetic modifiers affect ovarian cancer risk may help improve personalized risk prediction, guide prevention and surveillance strategies, and provide new insights into disease mechanisms and potential therapeutic targets.

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.