Evidence for an ancient BRCA 1 pathogenic variant in inherited breast cancer patients from Senegal

Abstract

BRCA1 and BRCA2 are the most incriminated genes in inherited breast/ovarian cancers. Several pathogenic variants of these genes conferring genetic predisposition have been described in different populations but rarely in sub-Saharan Africa. The objectives of this study were to identify pathogenic variants of the BRCA genes involved in hereditary breast cancer in Senegal and to search for a founder effect. We recruited after free informed consent, 27 unrelated index cases diagnosed with breast cancer and each having a family history. Mutation screening of the genes identified a duplication of ten nucleotides c.815_824dupAGCCATGTGG, (p.Thr276Alafs) (NM_007294.3) located in exon 11 of BRCA1 gene, in 15 index cases (allelic frequency 27.7%). The pathogenic variant has been previously reported in African Americans as a founder mutation of West African origin. Haplotypes analysis of seven microsatellites surrounding the BRCA1 gene highlights a shared haplotype encompassing ~400 kb between D17S855 and D17S1325. This haplotype was not detected in none of 15 healthy controls. Estimation of the age of the pathogenic variant suggested that it occurred ~1400 years ago. Our study identified a founder pathogenic variant of BRCA1 predisposing to breast cancer and enabled the establishment of an affordable genetic test as a mean of prevention for Senegalese women at risk.

Keywords: Breast cancer; Cancer genetics.

Fig. 1

Chromatographic sequence of the BRCA1gene exon 11 surrounding the identified pathogenic variant c.815_824dup.

Fig. 2. Pedigrees of six families carrying the BRCA1 pathogenic variant c.815_824dup10 identified by Sanger sequencing.

Blue color indicates individuals diagnosed with breast cancer. P: index case, E+: Individual with pathogenic variant, E−: Individual without pathogenic variant.

Fig. 3. 4% agarose gel electrophoresis of PCR products for BRCA1 pathogenic variant c.815_824dup10 genotyping.

PM molecular weight marker, TN DNA negative control, NM non-carrier index case, AB-FY-FGF-FW-ML-SN-WM-SM-NAG-AT: index cases carrying the mutation (AB-FY-FGF-FW-ML-AT belong to the first group of 15 index cases recruited and SN-WM-SM-NAG belong to the second group of 12 recruited index cases). This gel derived from a single experiment.