The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles.
We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis.
The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and “rare” BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women.
Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.
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We cordially thank patients and physicians, who participated in this study. We also thank the Russian Society for Clinical Oncology for the support of this investigation.
The study was supported by the Russian Foundation for Basic Research [Grant Nos. 20‐515-00002 and 19‐515-25001]. The analysis of breast cancer patients was partially supported by the research Grant #56223641 from Pfizer. A part of gene sequencing was supported by the Grant 075‐15-2019‐1669 from the Ministry of Science and Higher Education of the Russian Federation. The funding sources had no role in the study design, in the preparation of the manuscript or in the decision to submit the manuscript for publication.
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The authors declare that they have no conflicts of interest.
The study design was approved by the local Ethical Committee. All procedures performed in study were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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Sokolenko, A.P., Sokolova, T.N., Ni, V.I. et al. Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients. Breast Cancer Res Treat 184, 229–235 (2020). https://doi.org/10.1007/s10549-020-05827-8
- BRCA1 and BRCA2 testing
- Founder mutation
- Hereditary breast cancer
- Next-generation sequencing
- Ovarian cancer