New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients.

BACKGROUND: In Russia, more than 50,000 women are diagnosed with breast cancer (BC) every year. Russia is a multinational country - about 200 ethnic groups live on its territory. Khakass, Buryats, Tuvans and other ethnic groups show higher rate of increase in BC incidence and a younger age of first diagnosed BC compared to Caucasian ethnicities. We focused on Tuvan ethnic group to find specific genetic aberrations associated with BC. There are no BC prevention models as well as standards for the treatment of inherited BC in Tuvans. In this context, the search for genetic markers of early cancer detection and the development of criteria for therapy response are relevant. AIM: To identify hereditary mutations in BC-associated genes in Tuvan women. MATERIALS AND METHODS: 24 patients with early-onset BC (range, 25 to 46 years) were enrolled in the study. Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Next-generation sequencing was performed using the Illumina NextSeq500 System. RESULTS: In our study, one pathogenic mutation was detected in BRCA1 (rs80357868) gene (prevalence of 4%, 1/24). We identified the truncating 3875_3878delGTCT mutation of BRCA1 gene in Tuvans BC patient aged 34 years. We also detected three mutations that were probably damaging by PolyPhen2 and/or deleterious by SIFT in ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes. CONCLUSION: To the best of our knowledge, this is the first report that describes the highly pathogenic variant in the BRCA1 gene (rs80357868) and possibly damaging (PolyPhen2) germline variants in the ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes in young Tuvans BC patient.

[Ethnic aspects of hereditary breast cancer in the region of Siberia].

BACKGROUND: Ethnic diversity of the population in the region of Siberia suggests the existence of different germline mutations in the BRCA1/2 genes associated with breast and ovarian cancer in different ethnic populations, but spectrum of these mutations has not been studied. OBJECTIVE: Our aim was to evaluate the frequency of the most common mutations BRCA1/2 (BRCA1 5382insC, BRCA1 185delAG, BRCA1 4153delAG, BRCAI T300G, BRCA2 6174delT) in women diagnosed with breast cancer among indigenous people and newcomers living in Siberia. METHODS: We tested 1281 genomic DNA samples for the presence of BRCA1 5382insC mutation in patients diagnosed with breast cancer considering no family history. 72 patients having hereditary cancer signs were tested for the mutations BRCA1 185delAG, BRCA1 4153delAG, BRCA1 T300G, BRCA2 6174delT. RESULTS: Out of 765 patients of Slavic ethnic group, 27 women (3.5%) were carriers of allele BRCA1 5382insC. The frequencies of mutations in patients with signs of hereditary cancer were: 8.3% in group of young patients (under 40 years), 20.0% in patients with bilateral cancer and 5.7% in patients with family history of breast or ovarian cancers. We tested 516 BC patients residing on the territory of the Buryat-Aginsky district, Republics of Tyva and Altai. Out of them, there were 197 patients among the indigenous population (buryats, tuvinians, altaians), and 319 patients among newcomers (Slavic ethnics). Mutations BRCA1 5382insC were detected only in women from Slavic ethnic groups. The frequency of BRCA1 5382insC mutation was 6% in the group where family history was excluded and 14% in the group of patients with characteristics of family cancer. Allele BRCA1 5382insC was not found in indigenous breast cancer patients, although 59 patients had signs of hereditary cancer. In women from Slavic ethnic group, the BRCA1 185delAG, BRCA1 4153delAG and BRCA1 T300G mutations were detected in 9.1% of cases and were not found in patients among the indigenous population. CONCLUSION: studies of mutations in the BRCA1 gene in breast cancer patients from Siberia confirmed data on the high frequency of "founder mutation" BRCA1 5382insC in Slavic population and indicate the advisability of further studies to identify the genes responsible for the occurrence of hereditary breast cancer in the indigenous population.