Review of the results of mass screening for the BRCA1/2 gene mutations in patients with different types of malignant neoplasms

Background: germline mutations in the BRCA1 and BRCA2 genes are associated with a high risk of developing cancer of various localizations. Currently, the determination of BRCA status in such patients is important for choosing surgical tactics and determining indications for the administration of multiple chemotherapy drugs. Aim: to evaluate the results of mass genetic screening for mutations in the BRCA1 and BRCA2 genes in patients with various types of malignant neoplasms (MN). Patients and Methods: the results of genetic screening of 5043 patients who are reviewed in the study. The patients had the following diagnoses: breast cancer (BC, n=4216), ovarian cancer (OC, n=481), multiple primary malignant neoplasms (n=174), pancreatic cancer (n=96) and prostate cancer (n=75). Real-time PCR-based genetic testing for eight recurrent BRCA1/2 gene mutations specific for the Russian population was performed for all patients. The study of the entire coding sequence of the BRCA1/2 genes was carried out in 655 patients with negative screening results for mutations using high-resolution melting curve analysis, Sanger sequencing, and massively parallel sequencing. Results and Discussion: among 5043 cancer patients, the total frequency of BRCA mutations was 8%. In patients with BC the recurrent variants accounted for 6.7%, bilateral BC — 13.5%, OC — 17%, multiple primary malignant neoplasms (MPMN) — 13.1%, pancreatic cancer — 3.1%, while in patients with prostate cancer no mutations were found. The frequency of the c.5266dup mutation in the BRCA1 gene was 5.63%. Forty nine patients (0.97%) were carriers of another mutation — p.C61G, which is specific for the Slavic populations. Other variants were found much less frequently (0.1–0.38%). Thus, screening for common mutations helped to determine the prevalence of each of the variants and proved a high frequency of c.5266dup and p.C61G mutations. The analysis of the coding sequence of the BRCA1/2 genes in 655 patients revealed pathogenic mutations (class 5) in 13% of cases. The prevalence of rare variants in patients with BC was 11.1%, bilateral BC — 26.5%, OC — 14.9%, МPМN — 31%, pancreatic cancer — 2.3%, and prostate cancer — 2.5%. In the BRCA1 gene, 41 unique clinically significant mutations were found, and four of them were repeated in unrelated patients. In the BRCA2 gene, 29 unique clinically significant mutations were found, five of which were repeated. Moreover, 19 missense mutations were detected which, according to the databases, were categorized as variants with unknown clinical significance (class 3). They were analyzed using seven pathogenicity prediction algorithms. As a result, five mutations were interpreted by the most algorithms as likely pathogenic or pathogenic (class 4/5), five mutations were re-assessed as variants with unknown significance, and nine variants were identified as clinically insignificant. Conclusion: thus, the Russian population is characterized by the presence of multiple recurrent mutations, while in patients with different cancer types the prevalence of c.5266dup and p.C61G is significantly higher than the prevalence of other variants. Analysis of recurrent variants in the BRCA1/2 genes enables identification of approx. 80% of carriers of the pathogenic mutations. The use of the panel kit which includes such variants is considered as an inexpensive and sensitive algorithm for the first-step screening of the BRCA1/2 genes. A follow-on investigation of all coding gene regions (sequencing) is feasible for the studied patient groups and can significantly increase the detectability of pathogenic mutations in the BRCA1/2 genes. KEYWORDS: BRCA1 mutations, BRCA2 mutations, breast cancer, ovarian cancer, malignant neoplasms. FOR CITATION: Stroganova A.M., Pospekhova N.I., Golovina D.A. et al. Review of the results of mass screening for the BRCA1/2 gene mutations in patients with different types of malignant neoplasms. Russian Medical Inquiry. 2022;6(6):297–308 (in Russ.). DOI: 10.32364/2587-6821- 2022-6-6-297-308.