Abstract 3929: Comparative genomics of breast cancer in indigenous African and western populations first results from the E-Predict study

Abstract Breast cancer (BC) stands as the foremost female malignancy globally and is the most prevalent cancer in numerous developing countries, particularly in sub-Saharan Africa (SSA). Over the past decade, significant strides in comprehending the pathobiology of the disease and tumour dynamics have greatly enhanced treatment options, particularly in industrialized nations. Regrettably, SSA countries have witnessed only marginal, if any, improvements, with mortality rates surpassing incidence rates. Unfavourable outcome, early onset and high-grade tumours are predominant in SSA. Despite these challenging clinical phenotypes, there is currently a limited understanding of the primary molecular drivers, primarily due to a dearth of reliable data. Furthermore, there is a paucity of research conducted in, and pertinent to, the challenges of the disease in low-income countries (LICs), despite a rising incidence and higher mortality-to-incidence ratios. We thus established an international translational cancer research consortium in five distinct African countries. This initiative has contributed to the creation of a high-quality repository of biomaterials. Additionally, we have conducted whole exome sequencing on the initial 100 cases of breast cancer, comparing the molecular architecture of these tumors with data from The Cancer Genome Atlas (TCGA). We examining and compared the clinical disease phenotypes between indigenous African women and Western patients. A higher proportion of grade III tumors was observed in African patients aged between 30 to 59 years as compared to other patients within the same age group. In comparative molecular analyses, we found a significantly elevated tumor mutational burden in African patients (median of 15/MB) in contrast to other populations within the TCGA (median ~ 0. 7/MB). Gene sets featuring co-occurring mutations, predicted to be associated with survival using the TCGA dataset, showed high mutation rates in the African cohort. Notably, co-occurring mutations between PIK3CA and genes linked to genomic instability, such as BIRC6 (HR: 11. 7, p = 2. 7e-05), KMT2C (HR: 4. 7, p = 4. 01e-04), NEB (HR: 3. 84, p = 0. 48), and PCLO (HR: 4. 9, p = 0. 016), among others, strongly correlated with poor overall survival and were highly mutated within the African cohort. Interestingly, within the TCGA, patients with early breast cancer onset exhibit twice as many mutations in KMT2C, a gene known for its association with DNA damage repair, genomic instability, and showed an improved response to immune checkpoint inhibition. These initial findings suggest that breast cancer genomics in indigenous African populations may exhibit substantial differences, potentially warranting consideration for distinct therapeutic modalities for these patients. Citation Format: Smiths Sengkwawoh Lueong, Pamela Derliche Tonouo Derliche Tonouo, Arnol Auvaker Tiofack, Rovaldo Nguims Kenfack, Jules Roger Kuiate, Esther Dina Mbassi, Sidonie Noa Ananga, Etienne Okobalemba Atenguena, Gustave Simo, Abdel Jelil Njouendou, Walters Ndaka, Zacharie Sando, Emmanuella Mayemi, Rachel Tayou, Gilles Gael Aghoagni, Anne Sango, Benjamin Pokam, Augustin Tozoula Bambara, Jens T. Siveke. Comparative genomics of breast cancer in indigenous African and western populations first results from the E-Predict study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3929.