Abstract 1008: Genetic predisposition to breast cancer in Senegal: mutations of the <i>BRCA</i>1 and <i>BRCA2</i> genes

Abstract Background: BRCA1 and BRCA2 are the most incriminated genes in inherited breast and ovarian cancers. Several pathogenic variants of these genes conferring genetic predisposition have been described in different populations but rarely in subsaharan 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. Methods: We recruited after free informed consent, 46 unrelated index cases diagnosed with breast cancer and each having a family history, a control population of 90 healthy women and 80 women diagnosed with sporadic breast cancer and 36 patients diagnosed without a known family history of breast cancer at under 50 years All BRCA1 and BRCA2 exons were Sanger sequenced for the first 15 index cases recruited. For the following 31 index cases and healthy relatives and controls, the recurrent pathogenic variant of BRCA1 identified in the first group was genotyped by PCR. To search for a founder effect of the recurrent pathogenic variant of BRCA1, haplotype analysis of 7 microsatellites encompassing the gene was performed in 10 selected index cases with the pathogenic variant and 15 unrelated healthy controls. Mutation age was estimated using the following equation: G = logδ /log (1 - θ). Results: Mutation screening identified a recurrent duplication of 10 nucleotides c.815_824dupAGCCATGTGG, (p.Thr276Alafs) of BRCA1, in 26 index. Allelic frequency was estimated at 28, 26% compared to sporadic breast cancer cases (5%) healthy controls (0.55%) The variant was also found in 8 out of 36 patients diagnosed without a known family history of breast cancer at under 50 years of age (allelic frequency estimated at 11.11%) Haplotype analysis showed a shared haplotype encompassing approximately 400 kb. Estimation of the age of the pathogenic variant suggested that it occurred approximatively 1400 years ago and confirm a West African origin. The variant was also detected in healthy relatives of selected families. The genotyping method is now available as a first screening test in women at risk. For BRCA2 gene, a novel pathogenic variant, c.5219 T &amp;gt;133 G; p.(Leu1740Ter) was identified in a proband from a consanguineous family along with three sisters and one daughter of the index case. Conclusion: 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. We will screen for the variant BRCA1: c.815_824dup in Senegalese patient diagnosed with breast, ovarian, prostate and pancreatic cancers. Citation Format: Jean Pascal Demba Diop. Genetic predisposition to breast cancer in Senegal: mutations of the BRCA1 and BRCA2 genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1008.