BRCA1 mutations in Brazilian patients

Abstract

BRCA1 mutations are known to be responsible for the majority of hereditary breast and ovarian cancers in women with early onset and a family history of the disease. In this paper we present a mutational survey conducted in 47 Brazilian patients with breast/ovarian cancer, selected based on age at diagnosis, family history, tumor laterality, and presence of breast cancer in male patients. All 22 coding exons and intron-exon junctions were sequenced. Constitutional mutations were found in seven families, consisting of one insertion (insC5382) in exon 20 (four patients), one four base-pair deletion (3450-3453delCAAG) in exon 11 resulting in a premature stop codon (one patient), one transition (IVS17+2T > C) in intron 17 affecting a mRNA splicing site (one patient), and a C > T transition resulting in a stop-codon (Q1135X) in exon 11 (one patient). The identification of these mutations which are associated to hereditary breast and ovarian cancers will contribute to the characterization of the mutational spectrum of BRCA1 and to the improvement of genetic counseling for familial breast/ovarian cancer patients in Brazil. Key words: BRCA1, breast cancer, ovarian cancer. The Breast Cancer Linkage Consortium dataset indicates that the proportion of familial breast and ovarian cancers associated to BRCA1 or BRCA2 may be as high as 98% (Martin et al., 2001). Mutations in BRCA1 account for 45% of families with multiple cases of breast cancer and for at least 80% of families with early-onset breast and/or ovarian cancer (Miki et al., 1994). Moreover, 88% of families with at least four cases of early-onset breast cancer and one case of ovarian cancer are related to mutations in BRCA1 and BRCA2 (Unger et al., 2000). Furthermore, germ line BRCA1 or BRCA2 mutation carriers also have an increased risk of developing other cancers in prostate, stomach, colon, pancreas, fallopian tubes and uterus when compared to the general population (Offit, 1998;Brose et al., 2002). However, the alternative possibility of mutations in other, still unidentified susceptibility genes with low penetrance or chance clustering in families with multiple cases of breast/ovarian cancer without mutations in BRCA1 or BRCA2 remains to be determined.More than 800 different mutations were reported in BRCA1, and most of them are listed in the Breast Cancer Information Core (BIC -http://research.nhgri.nih.gov/bic/). Mutation carriers have an increased risk of developing breast cancer at different ages, with estimates of approximately 37% up to 40 years, 66% up to 55, 73% up to 70, and 82% over their entire lifetime (Hall et al., 1990;Brose et al., 2002). As for ovarian cancer, the risk was estimated to be 29% up to 50 years and 40% up to 70 years (Ford et al

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

“…This Ashkenazi Jewish founder mutation [34,35] has been described in Dutch, Russian, French and many other populations, and a recent study showed that 245 carriers from 14 different populations presented the same haplotype, suggesting a single founder origin [36]. Indeed, this is one of the most common mutations identified in Brazilian patients to date [22,24,25], and Gomes et al [22] found 5382insC in 56% of all BRCA mutation carriers, and a very similar frequency (57%) was described by Lourenço et al [37]. A 2008 study demonstrated that seven Brazilian 5382insC carriers all shared the same haplotype [38].…”

Prevalence and impact of founder mutations in hereditary breast cancer in Latin America

“…The high prevalence of c.5266dup was described initially in Ashkenazi Jews, and this mutation has subsequently been described in other populations from Central and Eastern Europe. Haplotype studies have demonstrated a common origin of this mutation in European populations, and several authors have described its occurrence in Brazilian breast cancer patients (Lourenço et al , 2004; Dufloth et al , 2005; Gomes et al , 2007). More recent studies indicate that the mutation was introduced into the Ashkenazi Jewish genetic pool approximately 400–500 years ago in Poland, but the mutation originated from a single common European ancestor long before (Hamel et al , 2011).…”

Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

“…Only two reports from Brazilian breast-cancer affected patients have suggested that a founder BRCA1 mutation, c.5266dup, may be encountered at a significant prevalence [16,17]. This mutation is the second most common mutation described in the Breast Cancer Information Core (BIC) database [28] for HBOC families worldwide.…”

“…The women enrolled in the study were not selected for a family history of the disease, and their ancestry was not described. A previous study [16] of 47 unrelated breast cancer-affected women from Rio de Janeiro with a family history of cancer suggestive of the HBOC syndrome had already identified the BRCA1 c.5266dup mutation in a significant proportion of the mutation-positive patients (four in seven). Interestingly, none of them reported Jewish ancestry.…”