A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia

Pathogenic mutations in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose (PARP) inhibitors. In many countries, their detection includes patient prescreening with quantitative PCR (qPCR) identifying several founder mutations. In Russia, eight mutations are included in such tests, among which c.5266dup (5382insC) is the most frequently identified one. Here, we showed the distribution of 1406 pathogenic or likely pathogenic mutations in BRCA1/2 genes identified in ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. The most of mutations were detected with qPCR, for qPCR mutation negative samples, targeted next-generation sequencing (NGS) covering whole coding sequences of the genes was applied. As expected, the most abundant mutations were c.5266dupC (41.0%), c.4035delA (7.0%), c.1961delA (6.3%), c.181T>G (5.2%), c.3756_3759delGTCT (1.8%), c.3700_3704delGTAAA (1.5%), and c.68_69delAG (1.5%). However, we identified several mutations which were more frequent than the founder c.5946delT mutation (also known as 6174delT, 0.5% of participants): c.5152+1G>T (1.2%), c.1687C>T (1.0%), c.4689C>G (0.9%), c.1510delC (0.6%), c.2285_2286delGA (0.6%) in the BRCA1 gene; and c.5286T>G (1.2%), c.2808_2811delACAA (0.8%), c.658_659delGT (0.7%), c.7879A>T (0.6%), c.3847_3848delGT (0.6%) in the BRCA2 gene. Having developed an NGS-targeted panel on SNPs flanking BRCA2 c.5286T>G, we showed the founder effect for this mutation and suggested that it arose about 700 years ago that is twice later that it is thought for the c.5266dupC. The total occurrence of mutations identified in at least 10 participants (13 mutations) was only 70%. To our knowledge, eighty-nine mutations (identified in 8% of participants) have not been described previously. Thus, this study may help in improving prescreening qPCR tests and extend our knowledge about the BRCA1 and BRCA2 genes variability in ovarian cancer patients.