Introduction/Background*Approximately 15-30% high-grade serous ovarian carcinomas (HGSOCs) are caused by BRCA1/2 germ-line mutations. BRCA1/2 testing of consecutive HGSOC cases is logistically less complicated than the search for women with other clinical signs of BRCA1/2 syndrome (e.g., family history, young age or emergence of multiple cancers). We reasoned that this would be the most straightforward approach to identify ethnicity-specific mutations and investigated patients of Chechen origin. Chechens are a Northeast Caucasian ethnic group consisting of approximately 2 million people. This community is characterized by carefully preserved national and religious traditions, with a relatively low rate of interethnic marriage, and, consequently, high probability of persistence of founder alleles.
Methodology Coding sequences of BRCA1, BRCA2, ATM, TP53 and PALB2 genes were analyzed by next generation sequencing.
Result(s)*We initially included in the study 67 consecutive Chechen patients with HGSOC. Pathogenic BRCA1/2 alleles were detected in 12/67 (18%) HGSOC cases; all 8 women with BRCA1 mutation carried the same pathogenic variant (c.3627_3628delAG), while some genetic diversity was observed among BRCA2 heterozygous patients (p.Q3299X: n = 2; c.5345dupA: n = 1; c.7408_7409delTT: n = 1). Given the high frequency of mutations in BRCA1 gene, we added to the study 44 consecutive patients with triple-negative breast cancer. This effort relied on the fact, that BRCA1 is specifically associated with the triple-negative phenotype of breast cancer disease; 3 (7%) additional BRCA1 mutation carriers (c.3627_3628delAG: n = 2; c.1338_1339delAG: n = 1) were revealed. All patients with the BRCA1 c.3627_3628delAG pathogenic variant also carried linked c.1067G>A (p.Q356R) polymorphic substitution; therefore, BRCA1 c.3627_3628delAG is indeed a founder allele, but not a mutational hot spot. In addition to BRCA1/2, one HGSOC patient carried ATM truncating variant (p.Q1171X). There were no instances of PALB2 or TP53 germline alterations.
Conclusion*This is a small-scale study, which resulted in convincing demonstration of a strong founder effect in Chechen women with hereditary breast-ovarian cancer. Genetic testing of non-selected HGSOC patients allows highly efficient analysis of ethnicity-specific spectrum of BRCA1/2 mutations.