Screening of the founder pathogenic variants BRCA1 and BRCA2 in Russian metropolitan women.

backgroundHereditary cancer and associated high risk genetic variants accountable for 5-10% of all breast cancer cases carry a significant burden on the health system and the pathogenic variants carriers. The harm from these factors can be significantly reduced through the timely detection of genetic alterations and implementation of health monitoring programs for pathogenic variants carriers.

methodsWe conducted a population-based genetic screening of unselected women residing in a large metropolitan area in 2018. Testing targeted eight recurrent BRCA1/2 founder pathogenic variants using validated real-time PCR assays. Women with a detected variant were invited into a structured prospective surveillance program with standardized capture of clinical outcomes. The primary outcome was the prevalence of BRCA1/2 founder variants; secondary outcomes included age and family-history profiles, adherence to surveillance, and cancer incidence and stage among carriers. Analyses used descriptive summaries, χ² or Fisher's exact tests for proportions, Mann-Whitney tests for continuous variables, and risk ratios with 95% confidence intervals.

resultsThe study included a large cohort of 107,300 women. 402 identified pathogenic variant carriers were offered consultations by a geneticist and regular health monitoring, 94.3% of them agreed to participate and made a median of two visits. Among 402 identified BRCA1/2 pathogenic variant carriers, 386 women (0.36%) had pathogenic variants in the BRCA1 gene and 16 women (0.01%) had pathogenic variants in the BRCA2 gene. The BRCA1 variant c.5266dup accounted for 66.2% of all pathogenic variant detected. BRCA1/2 pathogenic variants were significantly associated with a high incidence of cancer in both pathogenic variants carriers and their relatives. Only 27.2% of pathogenic variants carriers met clinical guidelines for genetic screening, while 6.3% of women without detected pathogenic variants were eligible for genetic testing. Through a follow-up medical surveillance program, the percentage of cancers detected at an early stage in pathogenic variants carriers increased from 65% to 93%.

conclusionsThe findings of this study highlight the critical need for improved genetic screening protocols to identify high-risk individuals effectively. By refining clinical guidelines and implementing comprehensive follow-up programs, healthcare systems can enhance early detection rates of cancers associated with BRCA1/2 variants, ultimately leading to better patient outcomes and personalized healthcare strategies.