Germline pathogenic variants in Russian breast cancer patients revealed by whole-genome sequencing

Introduction. In 20–25 % of cases of patients with hereditary forms of breast cancer (BC), pathogenic variants of the BRCA1 and BRCA2 genes predisposing to BC and ovarian cancer can be identified. Based on the results of previous Russian studies, a simple and inexpensive testing system using real-time polymerase chain reaction consisting of the 8 most frequently identified variants (mutations) in the BRCA1 and BRCA2 genes was developed. The use of targeted panels for high-throughput sequencing and whole genome sequencing for diagnosis of hereditary BC led to identification of a number of genes with pathological variants causing this pathology in patients and their relatives. Aim. To evaluate the profile and frequency of pathological variants in genes associated with tumor development in Russian patients with BC. Materials and methods. Analysis of the results of whole genome sequencing of samples from 1514 patients with BC and 5163 individuals without oncological diseases (control group) was performed. Results. A spectrum of mutations in the BRCA1 and BRCA2 genes, as well as pathogenic variants in other genes, were identified. Based on the results of whole genome sequencing a new panel was developed consisting of 10 most common mutations in the BRCA1, BRCA2, АТМ and PALB2 genes. Additionally, significant associations between pathogenic variants in the ATM gene with estrogen-positive luminal BC (р = 0.034) and pathogenic variants in the BRCA1 gene with triple negative BC (p 0.001) were found. Conclusion. In accordance with the obtained data, the new panel of the most common pathogenic variants includes BRCA1 (rs28897672, rs80357522, rs80357906, rs41293455, rs80358094), BRCA2 (rs28897756, rs80359604), АТМ (rs587782652) and PALB2 (rs180177143, rs515726123). Implementation of the new extended panel for identification of frequent mutations in Russian patients with BC in clinical practice will allow to identify up to 7.7 % of germline variants in a random sample.