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 have 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) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19-39%; BC: 6-13%). 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, and BRCA1 c.2907_2910delTAAA in Karachays. Some BRCA1/2 alleles, particularly BRCA2 c.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 HGSOC and BC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2 alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.

Keywords: BRCA1; BRCA2; Founder effect; Hereditary cancer; North Caucasus; Pathogenic variants.