Abstract
Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del) and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.
Highlights
5-10% of all breast cancer diagnoses are associated to germline mutations in highly penetrant cancer predisposition genes
The estimated prior probability of carrying a BRCA gene mutation was greater than 20% for 65 (44.8%) and 71 (49.0%) probands according to the Myriad mutation prevalence tables and the Penn II model, respectively
Sequencing of the two individuals with unequivocal BRCA1 rearrangements found by Multiplex Ligation-dependent Probe Amplification (MLPA) identified the exact breakpoints
Summary
5-10% of all breast cancer diagnoses are associated to germline mutations in highly penetrant cancer predisposition genes. Pathogenic variations in the coding region or in splice sites of the genes are found in, at most, two thirds of the families carrying BRCA mutations (Wera et al, 2003; Linger and Kruk, 2010) Several explanations for this observation have been proposed, including heterogeneous inclusion criteria with different stringencies, the existence of other dominant genes associated with the phenotype, and/or additive effects of multiple lower penetrance alleles. Several reports confirmed that BRCA rearrangements, in BRCA1, are quite frequent in HBOC families from selected countries (Preisler-Adams et al, 2006; Hansen et al, 2008; Kang et al, 2010; Ratajska et al, 2008; Stadler et al, 2010; Rudnicka et al, 2013; Pal et al, 2014) These mutations are scattered throughout the gene and most of them are deletions, duplications and triplications, as well as combined deletion/insertion events have been described. The higher prevalence of rearrangements in BRCA1, compared to BRCA2, has been attributed to its molecular structure, which is characterized by an extremely high density of intronic Alu repeats and by the presence of a duplicated promoter region containing a pseudogene that favors unequal homologous recombination events (Smith et al, 1996; Puget et al, 2002; Thomassen et al, 2006; Staaf et al, 2008)
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