Evidence for an ancient BRCA1 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.npj Genomic Medicine (2020) 5:8 ; https://doi.

Genetic Susceptibility to Breast Cancer in Sub-Saharan African Populations

“…One of three studies in Senegal identified a duplication of 10 nucleotides in the BRCA1 gene, c.815_824dup10, in 15 index cases from families with hereditary BC. 20 This duplication was located on the same microsatellite haplotype in all cases, had previously been reported in BC cases from France, Spain, and the United States, particularly in people of African or Hispanic descent, and is thus a founder mutation likely to be of West African origin. Whole-exome sequencing of 13 patients with BC in Kenya 19 detected five variants of uncertain clinical significance in BRCA1 and BRCA2 and a pathogenic variant in BRCA2 .…”

“…There were no GWASs among the 22 papers. The studies in this review included populations from 10 of the 46 SSA countries: Burkina Faso, 22 , 27 , 37 Cameroon, 21 Democratic Republic of Congo, 25 Ethiopia, 38 Kenya, 19 Nigeria, 23 , 28 , 30 , 32 , 33 , 35 , 36 Rwanda, 29 , 39 , 40 Senegal, 20 , 26 , 34 South Africa, 24 , 31 and Uganda. 21 …”

New Insights Into c.815_824dup Pathogenic Variant of BRCA1 in Inherited Breast Cancer: A Founder Mutation of West African Origin

“…In Africa, until October 2021, only one study from our team has reported the variant in patients diagnosed with inherited breast cancer ( 6 ). The variant was identified in 15 index cases with a family history of breast and/or ovarian cancer, out of 27 recruited.…”

“…In Sub-Saharan Africa, a few studies have reported specific founder mutations ( 4 , 5 ). Recently, we have reported a founder mutation, c.815_824dup, of the BRCA1 gene in Senegalese women with inherited breast cancer ( 6 ). This mutation is a duplication of 10 nucleotides (c.815_824dupAGCCATGTGG, p.Thr276AfsX14) located in exon 11 of BRCA1 according to the Human Genome Variation Society (HGVS) nomenclature and leads to a frameshift and a truncated protein.…”

Prevalence and Mortality of Triple-Negative Breast Cancer in West Africa: Biologic and Sociocultural Factors

“…Nonetheless, small-scale studies have shown that in WA women, TNBCs possess not only shared but also unique mutations. In Senegalese women with TNBC, Ndiaye et al 20 identified a 1,400-year-old pathogenic BRCA1 variant containing a 10-nucleotide duplication (c.815_824dupAGCCATGTGG) in exon 11. The same mutation was previously reported in AAs, suggesting a possible founder effect.…”