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Abstract
Introduction. In patients with breast cancer (BC) and ovarian cancer (OC) who belong to ethnic groups with relatively dense populations and a strong founder effect, analysis of ethnic-specific mutations in BRCA1 and BRCA2 may be a cost-effective alternative to sequencing the full coding sequences of these genes.
Aim. To characterize the spectrum of BC- and OC-associated pathogenic variants in patients of Kabardian and Balkar nationalities living in the Kabardino-Balkarian Republic (KBR) and to identify recurrent alleles.
Materials and methods. The study included 273 BC (n = 200) and OC (n = 73) patients: 221 Kabardian, 44 Balkar and 8 patients of mixed Kabardino-Balkarian origin. Information on ethnicity was provided by the patients. The coding sequences of the BRCA1 and BRCA2 genes, as well as PALB2, ATM and TP53 were analyzed using targeted next generation sequencing.
Results. In total, 39 BRCA1/BRCA2 pathogenic variants were identified in the study group. The frequency of mutations in the BC group was 13 % (n = 26). The was a higher prevalence of BRCA2 alleles compared to BRCA1 (BRCA1: 6/200 (3 %) vs. BRCA2: 20/200 (10 %), p = 0.007). In OCs, 8/73 (11 %) BRCA1 mutations and 5/73 (6.8 %) BRCA2 mutations were found. In the spectrum of pathogenic alleles, 84 % of the variants were recurrent. The most common allele, detected in both Kabardian (n = 6) and Balkar (n = 3) patients, was the missense variant BRCA2 c.7868A>G [p.His2623Arg]. Other recurrent pathogenic variants in this region included BRCA1 c.5266dupC (n = 5), c.1961delA (n = 4), BRCA2 c.993_994delAA (n = 4), c.8437G>T [G2813X] (n = 4), c.6486_6489delACAA (n = 4), c.8009C>A [p.Ser2670Ter] (n = 2). In Balkars, the only recurrent allele was BRCA2 c.7868A>G. Pathogenic ATM alleles were detected in 8 patients (3.0 %), with only one pathogenic variant occurring more than once (ATM c.8874_8877del [rs770704493]). Pathogenic and likely pathogenic variants of TP53 and PALB2 were not observed.
Conclusion. Thus, the spectrum of BC/OC-associated mutations in the studied region is characterized by a pronounced founder effect in relation to the BRCA2 gene. It can be argued that the BRCA2 mutation c.7868A>G [p.His2623Arg] is a major founder variant in Kabardians, and probably in Balkars.
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