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

Abstract

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 (r2=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.

Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations

“…Haplotype analysis in 11 unrelated carriers from seven countries Page 8 of 17 revealed a great difference among all families (although not statistically significant), suggesting different origins for this mutation [41]. Finally, we and others detected the BRCA1 c.3331_3334delCAAG (3450del4) mutation [23,24,26], which was previously described in Colombian patients, where its prevalence ranged from 1.6% in unselected breast cancer patients [30] to 73% of detected mutations among unselected ovarian cancer patients [11]. In Brazil, this mutation has already been seen [23,24,26].…”

“…The HISPANEL is organized into 5 multiplex PCR reactions and detects 59 BRCA1 and 55 BRCA2 mutations, including 15 mutations already described in Brazilian patients [21][22][23][24][25][26]. Results of the HISPANEL analyses were compared to data from an independent cohort of 193 unrelated probands from the same Page 5 of 17 region who met the same inclusion criteria and had full BRCA testing by either Sanger or next generation sequencing at commercial diagnostic laboratories.…”

Genomic Disparities in Breast Cancer among Latinas

“…25,29,30,72–80 Limited studies have been performed of non- BRCA genes in Latina breast cancer cohorts, leaving much to be learned about the prevalence and spectrum of mutations in these genes among Latinas with breast cancer (Table 1). 25,29,30,72–80 …”

Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review

“…Of these, two corresponded to mutation 6633del5 reported in two nonrelated women. Recently, Felix et al [18] reported two new recurrent mutations in gene BRCA1 identified in 106 patients from the north of Brazil, mutation c.211A.G (p.R71G) followed by mutation 3450del4, which was previously reported as a founder in the Colombian population by Torres et al [12].…”