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.
Highlights
With a rapidly evolving incidence, breast cancer is currently the first female cancer in sub-Saharan Africa followed by cervical cancer.[1]
Mutation screening identified a recurrent pathogenic variant at heterozygous state of the BRCA1 gene in 15 probands out of 27 recruited. This is a duplication of ten nucleotides (c.815_824dupAGCCATGTGG, p.Thr276Afs) located in exon 11 of BRCA1 according to the HGVS nomenclature (Fig. 1)
This pathogenic variant leads to a frameshift and a spurious stop codon 14 amino acids further down. It was detected in six index cases of a first group of 15 index cases by mutation screening of all coding exons of BRCA1 gene, and later in nine additional index cases from a second group of 12 patients by PCR genotyping (Supplementary Fig. 1)
Summary
With a rapidly evolving incidence, breast cancer is currently the first female cancer in sub-Saharan Africa followed by cervical cancer.[1]. Sub-Saharan Africa are triple negative, prognostic stage III tumours, with average age at diagnosis at late 40 s, resulting in a high-mortality rate.[2,3] Overall, 5–10% of breast cancers are inherited and could be associated with ovarian cancers. Women who have inherited mutations in BRCA1 or BRCA2 are at higher risk of developing breast and/or ovarian cancers.[4] Risk increased with the number of affected women within the family, early age at diagnosis and the degree of relationship with other affected women.[5,6,7] The cumulative risk of breast cancer by age 80 years was estimated to 72% for BRCA1 carriers and 69% for BRCA2 carriers. Cumulative risk at age 80 years was estimated to 44% for BRCA1 carriers and 17% for BRCA2 carriers.[5,6,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
