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Abstract
Introduction. We have previously demonstrated that hereditary breast cancer (BC) and ovarian cancer (OC) in patients of non-Slavic ethnicities from the North Caucasus republics exhibit a pronounced founder effect for mutations in the BRCA1 and BRCA2 genes.
Aim. The aim of this study was to characterize the frequency and spectrum of pathogenic germline variants in BRCA1, BRCA2, ATM, PALB2, CHEK2, RAD51B/C/D, and TP53in BC and OC patients from the Republic of North Ossetia — Alania.
Materials and Methods. The study included 384 DNA samples from peripheral blood lymphocytes of patients (301 BC cases, median age 46 years; 83 OC cases, median age 58 years) who underwent genetic testing at the N.N. Petrov National Medical Research Center of Oncology (2017–2026). Exons and exon-intron boundaries of the BRCA1, BRCA2, TP53, ATM, PALB2, CHEK2, and RAD51B/C/D genes were analyzed by targeted next-generation sequencing.
Results. Pathogenic BRCA1/2 variants were identified in 27 patients (5.3 % in the BC group; 13.3 % in the OC group), with a predominance of BRCA2 mutations (4.7 % in BC vs. 8.4 % in OC). Recurrent BRCA2 variants included c.6341del, c.9413dup, c.793 + 1G > T, c.7805 + 2T > C, and p.Gln3299Ter. Pathogenic ATM (1.8 %) and PALB2 (1.0 %) variants were found exclusively in the BC group, with the recurrent PALB2c.1592del allele. The frequency of CHEK2 mutations was 1.8 % in BC and 2.4 % in OC. Mutations in the RAD51B/C/D genes were represented exclusively by the RAD51C nonsense variant c.577C > T (p.Arg193Ter), with a significantly higher frequency in the OC group (9.4 %) compared to the BC group (1.1 %) (p = 0.004). No pathogenic germline TP53 variants were detected.
Conclusion. A significant proportion of hereditary ovarian cancer in North Ossetia — Alania is attributable to mutations in the RAD51C gene. We identified a major "Ossetian" founder variant, RAD51C p.Arg193Ter. This represents the first observation in Russia demonstrating the predominance of a mutation in a non-BRCA gene within the hereditary predisposition structure for breast and ovarian cancer.
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