Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus

Abstract Background Mountain areas of the North Caucasus host several large ethnic communities that preserved their national identity over the centuries. Methods This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. Results A significant contribution of BRCA1/2 pathogenic variants (PVs) in HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 18.8–38.5%; BC: 6.3–13%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG in Chechens, BRCA2 c.6341delC in North Ossetians, BRCA2 c.5351dupA in Ingush, BRCA1c.2907_2910delTAAA in Karachays, etc. Some BRCA1/2alleles, particularly BRCA2c.9895C>T, were shared by several nationalities. ATM PVs were detected in 14 patients, with c.1673delG and c.8876_8879delACTG alleles occurring twice each. PALB2 heterozygosity was observed in 5 subjects, with one variant seen in 2 unrelated women. Conclusion This study adds to the evidence for the global-wide contribution of BRCA1/2 genes to BC and HGSOC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.