In this study, we aimed at reporting the frequency of BRCA, CHEK2 and TP53 mutations in our high risk breast/ovarian cancer population, in order to determine the role of these genes testing in breast cancer risk assessment.
Total DNA of 484 unrelated cases and 180 relatives were sequence using either Sanger (564) or NGS (100) for BRCA1/BRCA2, CHEK2 and TP53 mutations. While 64.5% (312/484) of the population studied belong to jewish ethnicity, the remaining patients were european-amerindians.
Of the 484 probands analyzed, 15.9% were BRCA1/BRCA2 mutation carriers, 9.7% in BRCA1, 6% in BRCA2 and one patient was double heterozygous. Overall, 18.9% of the jewish patients presented ashkenazi founder mutations and 9.9% of european-amerindian population was positive for BRCA mutations. The c.66_67delAG was the most frequent alteration, representing 34.2% of all mutations identified. Pathogenic variants in CHEK2 and TP53 genes were present in 4% and 1.1% of our european-amerindian cases. Eighteen pathogenic variants different from ashkenazi panel were identified in BRCA, three were novel and twelve not previously reported in argentinian population. Twenty-seven variants of uncertain significance were found.
An association between genetic ancestry and mutational profile was observed only in the Jewish population. The 66.7% of the pathogenic variants found in our non-jewish cohort were in BRCA2. Our results confirm the high level of admixture present in argentinian population, and highlight the detection of novel variants that could be typical of our region. The knowledge of them is relevant to improve patient risk assessment.
Clinical trial identification
Legal entity responsible for the study
Centro Nacional de Genética Médica, ANLIS, Malbrán, Ministerio de Salud de la Nación
All authors have declared no conflicts of interest.