2263P - Ethnicity-specific distribution of BRCA1, BRCA2, PALB2 and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus

Background

Mountain areas of the North Caucasus host several large ethnic communities, which managed to preserve their national identity through the centuries. The way of life characteristic for people from this region allows to expect high contribution of founder alleles, with an unique spectrum of pathogenic variants characteristic for each of the ethnic groups.

Methods

This study involved high-grade serous ovarian cancer (OC) and breast cancer (BC) patients from Dagestan (OC: 37; BC: 198), Kabardino-Balkaria (OC: 68; BC: 155), North Ossetia (OC: 51; BC: 104), Chechnya (OC: 68; BC: 79), Ingushetia (OC: 19; BC: 103), Karachay-Cherkessia (OC: 13; BC: 47), and several Armenian settlements (OC: 12; BC: 79). 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

Significant contribution of BRCA1/2 pathogenic variants in the OC and BC development was observed across all North Caucasus regions (OC: 18-31%; BC: 7-14%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG [p.Glu1210fs] in Chechens, BRCA2 c.6341delC [p.Pro2114fs] in North Ossetians, BRCA2 c.5351dupA [p.Asn1784fs] in Ingush, BRCA1 c.2907_2910delTAAA [p.Lys970fs] in Karachays, etc. Some BRCA1/2 alleles, particularly BRCA2 c.9895C>T [p.Gln3299Ter], were shared by several nationalities. ATM pathogenic variants were detected in 14 patients, with 2 alleles occurring twice each. PALB2 heterozygosity was observed n 6 subjects, with one variant seen in 2 unrelated women.

Conclusions

This study adds to the evidence for global-wide contribution of BRCA1 and BRCA2 genes in BC and OC morbidity, although the spectrum of their pathogenic alleles is a subject of ethnicity-specific variations. Data on founder BRCA1/2 mutations may be considered while adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This study has been supported by the Russian Science Foundation [grant number 21–75-30015].

Disclosure

All authors have declared no conflicts of interest.