Spectrum of pathogenic variants associated with hereditary breast and ovarian cancer in the Republic of Dagestan

Background. A significant proportion of patients with breast cancer (BC) and ovarian cancer (OC) are carriers of pathogenic variants in the genes of hereditary cancer syndromes. Most often, hereditary forms of BC and OC are associated with alterations in the BRCA1 and BRCA2 genes. At the same time, the spectrum of mutations varies among representatives of different ethnic groups, reflecting the features of the genetic load. The population of Dagestan has unique genetic landscape due to historical and demographic factors. The republic is one of the most multinational regions of the Russian Federation, where representatives of numerous ethnolinguistic groups live (Avars, Lezgins, Dargins, Laks, etc.), which suggests the existence of recurring pathogenic genetic variants, i.e., the presence of a “founder effect” among representatives of the Dagestan peoples. The aim of this work was an in-depth study of hereditary breast and ovarian cancer in the Republic of Dagestan. Material and Methods. The study included 610 patients representing various nationalities of the Republic of Dagestan. The coding sequences of BRCA1, BRCA2, PALB2, ATM, TP53, CHEK2, NBN, BRIP1, BARD1, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L were analyzed using targeted high-throughput sequencing. Results. The most frequent pathogenic variants in the study group were BRCA1 c.66dup, c.115T>C [p.Cys39Arg], c.4709del and BRCA2 p.Gln3299Ter and c.5621_5624del. Among other genes, only CHEK2 c.817_818del pathogenic allele was recurrent. Several ethnospecific variants of the BRCA1 and BRCA2 genes were identified, which were dominant in certain ethnic groups in the Republic of Dagestan. In patients of Lezgin origin, the BRCA1 c.66dup allele was predominant (7/12 (58 %) of all BRCA1/2 variants in this ethnic group), and in Dargins, BRCA1 c.4709del (4/12 (33 %)). Several recurrent variants were identified in Avars, all of which in the BRCA2 gene: p.Gln3299Ter (8/21 (38 %) of all BRCA1/2 variants in Avars), c.5621_5624del (5/21 (24 %)), p.Arg2659Lys (3/21 (14 %)). A founder effect was also observed in the Laks: all cases of BRCA1/2 mutations were represented by a single BRCA2 allele (c. 429del). The BRCA1 p.Cys39Arg variant was found in several ethnic groups: Kumyks, Avars, and Dargins. In patients of Tabasaran origin, pathogenic variants were not identified. Conclusion. The diversity of the identified mutations reflects the long-term migration processes and ethnic uniqueness of the Dagestan population.