Algorithm of molecular genetic investigation to identify hereditary BRCA-associated breast cancer

Background: About 30%  of cases of hereditary breast cancer (BC) are associated with the BRCA1 and BRCA2 gene mutations. The absence of the programs of mandatory genetic screening for hereditary BRCA-associated BC in Russia, as well as of an algorithm for molecular genetic testing does not allow fully accomplishing the necessary preventive, diagnostic and medical measures.

Aim: To elaborate an algorithm for molecular genetic testing of BC patients in order to improve the efficacy of identification of the hereditary nature of the disease.

Materials and methods: The study is based on the analysis of the results of molecular genetic testing of 3826 BC patients aged from 22 to 90 years, who were examined and treated in the Russian Research Center of Roentgenoradiology (Moscow) from 2010 to 2016. At the first stage of the study, germinal mutation in the BRCA1 and BRCA2 genes prevalent in the Russian population were identified by the real-time polymerase chain reaction (PCR). At the second stage, we searched for rare genetic variants of these genes by the ‘next generation sequencing’ (NGS) method.

Results: The real-time PCR (the first stage) showed that the prevalence of the most typical for the Russian population mutations in the BRCA1 gene, associated with BC risk, was 3.5% (132/3826 BC patients). No carriers of the BRCA2 mutations were identified. Based on the analysis of a  questionnaire survey and primary medical documentation, a group of 717 patients was selected from the total cohort, who had clinical features of the hereditary disease (CFHD). In this group, the BRCA1 and BRCA2 gene mutations were found in 126 patients (17.6%). At the second stage, a group of 193 patients with CFHD and no BRCA1 and BRCA2 mutations prevalent in the Russian population was investigated by NGS. Rare pathogenic mutations of these genes were found in 27  patients (14%). In total, it may be concluded that at least 30% of the BC patients with CFHD have germinal mutations in the BRCA1 and BRCA2 genes. Based on the data obtained, we have developed the algorithm of molecular genetic testing of BC patients aimed at identification of the hereditary nature of the disease.

Conclusion: The high frequency of mutations in the BRCA1 and BRCA2 genes found in this study in BC patients with CFHD confirms the necessity of genetic testing for this hereditary disease. The information on its hereditary nature allows for the introduction of essential therapy modification with a personalized approach. Regular follow-up of patients with hereditary BC and prevention of new BC cases and other cancers (ovarian, gastric, pancreatic and prostate cancer, as well as melanoma) in their relatives with BRCA1 and BRCA2 mutations have to be implemented by a multidisciplinary team (specialists in mammology, gynecology, oncology, medical genetics, chemotherapy and psychotherapy).