Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population

Considering the importance of BRCA1, BRCA2, CHEK2 and TP53 in the development of hereditary early-onset breast and ovarian cancer and that the genetic susceptibility profile of the Northeast population from Brazil has never been analyzed, this study aimed to verify the frequency of mutations of clinical significance in these genes in high-risk hereditary breast and ovarian cancer (HBOC) syndrome patients from that region. DNA samples from 106 high-risk unrelated patients mostly from Bahia, the biggest state in the Northeast region, were analyzed. These patients underwent full BRCA1 gene sequencing, screening for common founder mutations in the BRCA2, CHEK2 and TP53 genes and genetic ancestry analysis with nine ancestry informative markers. The positive results were confirmed by two sequencing reactions. Three mutations of clinical significance were found: BRCA1 p.R71G (4.71%), 3450del4 (3.77%) and TP53 p.R337H (0.94%). The genetic ancestry analysis showed a high European ancestry contribution (62.2%) as well as considerable African (31.2%) and Amerindian (6.6%) ancestry contributions (r(2)=0.991); this degree of heterogeneity was also significant in the population structure analysis (r=0.604). This population is highly admixed with a different spectrum of genetic susceptibility, with the Galician founder mutation BRCA1 p.R71G accounting for 50% of all identified mutations in high-risk HBOC patients. TP53 p.R337H was also significantly frequent; thus, the combined screening of BRCA1/2 and TP53 should be offered to high-risk HBOC patients from Northeast Brazil.