Background
Breast cancer survival rates in sub-Saharan Africa remain substantially lower than in high-income countries. The African Breast Cancer – Disparities in Outcomes (ABC-DO) study is a large, multi-country prospective cohort of over 2,100 women, designed to identify determinants of poor breast cancer outcomes and inform strategies to improve survival. Triple Negative Breast Cancer (TNBC), an aggressive subtype with limited targeted treatment options, is overrepresented in African populations, yet its underlying mutational processes remain insufficiently characterized.

Objectives
This sub-project aimed to (i) characterize mutational signatures of TNBC in an African cohort, (ii) compare these signatures with those observed in North American and European populations, and (iii) investigate potential associations between mutational signatures and breast cancer risk factors, including reproductive factors and obesity, as well as survival.

Methods
Whole-genome sequencing was performed on 19 fresh frozen TNBC tumor samples collected by the ARGO (African Research Group for Oncology) research group in Ile-Ife, Nigeria. Somatic mutations were identified and used for de novo mutational signature extraction with SigProfilerExtractor, based on non-negative matrix factorization (NMF). Extracted signatures were subsequently assigned to known COSMIC reference signatures using the Mutational Signature Attribution (MSA) tool based on non-negative least squares (NNLS). Signature-specific mutation counts were then regressed against epidemiological and clinical metadata using logistic regression models.

Results
Single base substitution (SBS) signatures were successfully extracted and decomposed into known COSMIC reference signatures, all previously reported in breast cancer. APOBEC-associated signatures SBS2 and SBS13 were detected in a high proportion of samples (80–90%), comparable to frequencies observed in public datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG). The homologous recombination repair deficiency signature SBS3 was more prevalent in the Nigerian cohort (~80%) compared to PCAWG breast cancer cases (~30%). Preliminary analyses suggest that there may be differences in the prevalence of certain signatures in the Nigerian cohort compared to a Scandinavian TNBC cohort. SBS3 mutations were associated with pre-menopausal status (p=0.039), whereas SBS5 mutation counts were associated with tumor stage (p=0.013).

Conclusions/Implications
This study confirms the presence of established breast cancer mutational signatures in African TNBC tumors. Some differences were observed in signature prevalence compared to non-African TNBC cohorts, but underlying mutational processes were broadly similar. These findings support the applicability of established precision oncology strategies to African populations and highlight the value of integrating genomic and epidemiological data to better understand breast cancer outcomes in underrepresented settings.