Abstract 1858: BRCA1 and BRCA2 sequence variants in Algerian breast/ovarian cancer families

Abstract

Abstract Abstract: Background: Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. To date, very few reports have been published about the spectrum of BRCA1 and BRCA2 mutations in the Algerian population. Here, we describe analysis of BRCA1 and BRCA2 genes in 57 individuals from 52 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast/ovarian cancer. Methods: The screening for variants in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 in Algerian patients was performed by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. All samples for which no pathogenic mutation was found were analyzed by MLPA (Multiplex Ligation-dependent Probe Amplification) for large deletions or duplications. To identify no synonymous amino acid changes likely to disrupt BRCA1 and BRCA2 genes function, we used a comparative evolutionary bioinformatic program, Polymorphism Phenotyping (Polyphen program). We used GeneSplicer program to identify the splice site alterations of new unclassified variants occurring in intron-exon boundaries of BRCA1 and BRCA2. Results: Three distinct pathogenic mutations, c.83_84delTG/p.Leu28ArgfsX12, c.181T>G/p.Cys61Gly, c.798_799delTT/p.Ser267LysfsX19 and two large rearrangements involving exon 2 (c.-19-? 80+?del/p.?) and exon 8 (c.442-? _547+?del/p.?) respectively, were detected in BRCA1 gene. Interestingly, the c.798_799delTT/p.Ser267LysfsX19 BRCA1 pathogenic mutation has been detected in two unrelated families. The BRCA1 exon 2 deletion reported here in this study seems has been never described before. Seventeen unclassified variants and polymorphisms were detected in BRCA1 gene (6 described for the first time). The new unclassified variant c.302-3C>T/p.? located near the acceptor splice site of BRCA1 intron 6 shows no splice alteration site. Two pathogenic mutations, c.1310_1313delAAGA/p.Lys437IlefsX22 and c.5722_5723delCT/p.Leu1908ArgfsX2 and 40 unclassified variants and polymorphisms (15 never described before) were identified in BRCA2 gene. Moreover, five new unclassified variants identified in the present study: one BRCA1 (c.4066C>A/p.Gln1356Lys) located in exon 11 and four BRCA2 (c.3868T>A/p.Cys1290Ser, c.4423A>G/p.Met1475Val, c.5472T>A/p.Asn1824Lys and c.5985C>A/ p.Asn1995Lys) located in exon 11, show a damaging PSIC score yielded by PolyPhen program and could be pathogenic. Conclusions: In this study, we attempted to delineate genetic component of hereditary breast/ovarian cancer among the Algerian population. This is the first screening of BRCA1 and BRCA2 mutations in Algerian breast/ovarian cancer families by using HRM and MLPA. These new findings will contribute to the assessment of the necessity of the preventive program for mutation carriers as part of the national public health policy in Algeria Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1858.