BRCA1 and BRCA2 germline mutations in Uruguayan breast and breast–ovarian cancer families. Identification of novel mutations and unclassified variants

Abstract

The aim of the present study was to analyze BRCA1 and BRCA2 mutations in Uruguayan families with breast and breast/ovarian cancer. Probands from 42 families with at least three cases of female breast cancer (BC) or two cases and subcriteria (paternal transmission, ovarian cancer, bilateral BC, male BC, Ashkenazi Jewish ancestry) in the same lineage, at least one diagnosed before age 50, were screened for germline mutations. PCR amplification of all exons and intron-exon boundaries were performed, followed by protein truncation test, heteroduplex analysis, and direct sequencing. We identified seven different truncating mutations in seven families, five in BRCA2 (three in site-specific BC families and two in breast-ovarian cancer families) and two in BRCA1 (one in a site-specific BC family and the other in a breast-ovarian cancer family). Both BRCA1 mutations (5583insT and 2687T>G) and one of the five BRCA2 mutations (3829insTdel35) were not previously reported. We also detected ten sequence variants of unknown significance, five of them not described before. The low frequency of BRCA1/2 mutations (0.17) is in agreement with that reported in studies which included families with similar selection criteria. However, the observed predominance of BRCA2 (0.12) over BRCA1 mutations (0.05) is in contrast with the higher proportion of BRCA1 mutations communicated for most previous studies, even those with a predominance of site-specific BC families. Meanwhile, it has been described in one Chilean and some Spanish and Italian reports, highlighting the strong dependence between the mutational spectra and the ethnicity of the population analyzed.

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

“…Two different studies conducted among Chilean patients revealed close prevalence rates: Gallardo et al [31] reported a mutation prevalence of 7.4% among HBOC patients, and GonzalezHormazabal et al [32] described, in a larger cohort of high-risk breast and/or ovarian cancer families, a prevalence of 7.1%. Finally, in Uruguay, 17% of 42 patients selected by family history carried a pathogenic germline mutation in Page 7 of 17 one of the BRCA genes [33]. Only two smaller studies (combined n=174) have performed comprehensive BRCA sequencing among Brazilian patients fulfilling NCCN criteria from the Brazilian State of São Paulo, wherein the HISPANEL detection rate would have been 7-11%, which corresponds to more than one third of the mutations detected by complete sequencing (detection rate 20-21%) [24,25].…”

Genetics, Tumor Features and Treatment Response of Breast Cancer in Latinas

“…Most Latin American studies identified a higher rate of BRCA1 than BRCA2 mutations [37], however studies from Costa Rica [43], Cuba [50], Puerto Rico [51] and Uruguay [46] reported the opposite finding. However, prevalence information could be underestimated due to methodology procedures.…”

“…Several recent studies have evaluated BRCA mutation in Latin American countries, and some of them have documented prevalence studies in high-risk population and in unselected invasive BC cases in Mexico (six total studies, 6.3-23.0% in high risk, 4.3% in unselected) [34][35][36], Brazil (eight studies, 3.4-22.5%, 2.3%) [37][38], Argentina (two studies, 16.2-58.3%, unknown) [33,39], Colombia (five studies, 14.3-24.5%, 1.2-4.5%) [40][41], Chile (two studies, 7.1-20.4%, unknown) [42], Costa Rica (one study, 4.5%, unknown) [43], Cuba (one study, 2.6%, unknown) [44], Peru (one study, 4.9%, unknown) [45], Uruguay (one study, 17%, unknown) [46], Venezuela (one study,17.2%, unknown) [47], Trinidad and Tobago (one study, unknown, 10.4%) [48] and The Bahamas (one study, 27.1%, unknown) [49]. Most Latin American studies identified a higher rate of BRCA1 than BRCA2 mutations [37], however studies from Costa Rica [43], Cuba [50], Puerto Rico [51] and Uruguay [46] reported the opposite finding.…”

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

“…In the study performed by Delgado et al [31], 42 families with at least 3 cases of female breast cancer or 2 cases and subcriteria (paternal transmission, ovarian cancer, bilateral breast cancer, male breast cancer, Ashkenazi Jewish ancestry) in the same lineage, at least 1 diagnosed before age 50, were screened for BRCA germline mutations. In total, seven different truncating mutations in seven families were identified, two in BRCA1 (5583insT and 2687T.G) and five in BRCA2 (4359ins6d, 5579insA, 3829insTdel35, 4088delA, and 1617delAG), but none were recurrent.…”