Full-Exon Pyrosequencing Screening of BRCA Germline Mutations in Mexican Women with Inherited Breast and Ovarian Cancer

Abstract

Hereditary breast cancer comprises 10% of all breast cancers. The most prevalent genes causing this pathology are BRCA1 and BRCA2 (breast cancer early onset 1 and 2), which also predispose to other cancers. Despite the outstanding relevance of genetic screening of BRCA deleterious variants in patients with a history of familial cancer, this practice is not common in Latin American public institutions. In this work we assessed mutations in the entire exonic and splice-site regions of BRCA in 39 patients with breast and ovarian cancer and with familial history of breast cancer or with clinical features suggestive for BRCA mutations by massive parallel pyrosequencing. First we evaluated the method with controls and found 41–485 reads per sequence in BRCA pathogenic mutations. Negative controls did not show deleterious variants, confirming the suitability of the approach. In patients diagnosed with cancer we found 4 novel deleterious mutations (c.2805_2808delAGAT and c.3124_3133delAGCAATATTA in BRCA1; c.2639_2640delTG and c.5114_5117delTAAA in BRCA2). The prevalence of BRCA mutations in these patients was 10.2%. Moreover, we discovered 16 variants with unknown clinical significance (11 in exons and 5 in introns); 4 were predicted as possibly pathogenic by in silico analyses, and 3 have not been described previously. This study illustrates how massive pyrosequencing technology can be applied to screen for BRCA mutations in the whole exonic and splice regions in patients with suspected BRCA-related cancers. This is the first effort to analyse the mutational status of BRCA genes on a Mexican-mestizo population by means of pyrosequencing.

Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

“…18–20 The current study demonstrates a remarkably high prevalence of BRCA mutations among breast and ovarian cancer cases not selected for family history (15% and 28%, respectively) in Mexico, which is higher than expected compared to previous data obtained from a population-based breast cancer registry series in the U.S., where the BRCA1 prevalence was 3.5% among Hispanics (n=393) aged <65, and 8.9% for patients <35 years. 21 Only our recently published high-risk clinic-based population (n=746) study had a higher prevalence (25%).…”

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

“…Even when comparing more comprehensive studies, in which the whole coding sequence and exon-intron boundaries of the BRCA genes were analyzed, significant heterogeneity exists in the mutation prevalence rates observed throughout Latin America. In Mexico, BRCA mutation prevalence varies from 10.2% in HBOC patients [28] to 21% (including large genomic rearrangements) in breast and ovarian cancer patients unselected for family history [20]. In Argentina, a prevalence of 28.3% was reported in series of breast or ovarian cancer patients selected for age at diagnosis and positive cancer family history [29], and a similar prevalence (24.5%) was found by Torres et al [30] in Colombian patients with breast and/or ovarian cancer and a family history of cancer.…”

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

“…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.…”