Abstract C047: Multiomics approaches to identify African-ancestry specific phenotypes of triple negative breast cancer
Authors: Martini Rachel , Chao Max , Chu Timothy , Stonaker Brian , Kyei Ishmael , Adjei Ernest , Bekele Mahteme , Gyan Kofi , Elemento Olivier , Robine Nicolas , Carpten John , Newman Lisa , Davis Melissa 
Published: December 2023

Abstract
Despite recent convergence of breast cancer (BC) incidence among African American (AA) and European American (EA) women, BC mortality remains 40% higher among AA women. This disparity is driven partly by BC heterogeneity, where distinct subtypes have differing prognosis and treatment modalities, defined by presence of estrogen and/or progesterone receptor (HR+), overexpression of HER2, or lack of all three biomarkers (triple negative BC (TNBC)). TNBC is the most aggressive subtype, diagnosed as late-stage disease and lacking targeted therapeutic options. TNBC represents ~10% of annual diagnoses, however prevalence is significantly higher among AA women. Our work in the International Center for the Study of Breast Cancer Subtypes (ICSBCS) revealed significant association of west African (AFR) ancestry and TNBC, where we report that Ghanaian and AA women have increased frequency of TNBC, compared to Ethiopian and EA women, and that TNBC patients have higher percentages of quantified AFR ancestry. To characterize AFR ancestry-specific TNBC phenotypes, we have employed transcriptomics and whole genome sequencing (WGS) methods. Our recent publication from an AFR ancestry enriched TNBC transcriptomics cohort (n = 26) leveraged genetic ancestry to identify 600+ AFR and 2000+ AFR sub-continental ancestry associated genes. Pathway analysis showed enrichment of immune cell trafficking and indicates distinct AFR ancestry phenotypes that can be leveraged for future therapeutic opportunities. Recently, we have completed WGS on 80+ AFR ancestry patients with TNBC disease (n = 59) and HR+ disease (n = 23); representing AA (n = 71), Ethiopian (n = 8) and Ghanaian patients (n = 3). TP53 was the most mutated gene, more commonly mutated among TNBC cases (83%) compared to HR+ cases (35%) (p &lt; 0.0001). HR+ had significantly more GATA3 (26%) and PIK3CA (30%) mutations compared to TNBC (0% and 9%, p &lt; 0.05). Prevalence of COSMIC mutational signatures shows higher Signature 1 among HR+ cases, and higher Signature 3 among TNBC cases (both p &lt; 0.05). Signature 3 is associated with DNA double-strand break repair and germline BRCA1/2 mutation status, where 9 TNBC cases have elevated homologous repair deficiency status. Our genomic work utilizes the reference genome, which is primarily sequenced from a single individual. With the African Pan Genome (APG), a set of 125,000+ contigs distinct from the reference genome, we have aligned RNAseq reads to the APG that failed to map to the reference genome. Successful APG alignment of a subset of reads indicates that genes are expressed from these distinct AFR sequences. We also identified CpG sites in contigs with gene expression, showing AFR ancestry specific regulatory regions in the previously unmapped genome. We are working to determine the significance of these in the tumor microenvironment. This work represents a comprehensive, AFR ancestry enriched cohort with multiple genomic data approaches that will allow us to further characterize TNBC disease and define actionable biomarkers and targets for women of African ancestry.
Citation Format: Rachel Martini, Max Chao, Timothy Chu, Brian Stonaker, Ishmael Kyei, Ernest Adjei, Mahteme Bekele, Kofi Gyan, Olivier Elemento, Nicolas Robine, John Carpten, Lisa Newman, Melissa Davis. Multiomics approaches to identify African-ancestry specific phenotypes of triple negative breast cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C047.