Anna P Sokolenko1,2, Tatiana N Sokolova3,4, Valeria I Ni3, Elena V Preobrazhenskaya3,4, Aglaya G Iyevleva3,5,4, Svetlana N Aleksakhina3,4, Alexandr A Romanko3,5, Alexandr A Bessonov6, Tatiana V Gorodnova7, Elena I Anisimova8, Elena L Savonevich9, Ilya V Bizin3, Ilya A Stepanov3, Petr V Krivorotko6, Igor V Berlev7, Alexey M Belyaev3,10, Alexandr V Togo3,5,4, Evgeny N Imyanitov3,5,10. 1. Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia. annasokolenko@mail.ru. 2. Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia. annasokolenko@mail.ru. 3. Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia. 4. Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical and Chemical Medicine, Moscow, Russia. 5. Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia. 6. Department of Mammology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia. 7. Department of Oncogynecology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia. 8. Leningrad Regional Cancer Hospital, St.-Petersburg, Russia. 9. Department of Obstetrics and Gynecology, Grodno State Medical University, Grodno, Belarus. 10. Department of Oncology, I.I. Mechnikov North-Western Medical University, Saint-Petersburg, Russia.
Abstract
BACKGROUND: The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles. METHODS: 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. RESULTS: 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 (BRCA1C61G, 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. CONCLUSION: 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.
Entities:
Keywords:
BRCA1 and BRCA2 testing; Founder mutation; Hereditary breast cancer; Next-generation sequencing; Ovarian cancer
Authors: G A Yanus; E L Savonevich; A P Sokolenko; A A Romanko; V I Ni; E Kh Bakaeva; O A Gorustovich; I V Bizin; E N Imyanitov Journal: Fam Cancer Date: 2022-05-21 Impact factor: 2.375