The somatic mutation profile of breast cancer in Uganda.
Authors: Menon Manoj , Niyonzima Nixon , Konnick Eric Q , Kasozi David , Adams Scott , Asea Jacqueline , Bakenga Alex , Basemera Diana , Henry Wannume , Kakungulu Edward , Mirembe Ruth , Muwanguzi Noreen , Mubiru Kelvin , Namagembe Rosemary , Nambuya Alice , Namuli Prossy , Natukunda Barbra , Okoche Lazarus , Towlerton Andrea , Orem Jackson 
Published: June 2023

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Background: Breast cancer, the most common cancer in sub-Saharan Africa (SSA), is characterized by poor survival compared with resource-rich regions. A variety of factors are responsible for this disparity and include late stage at presentation, limited diagnostic and therapeutic options, and potentially biologically more aggressive disease. The application of next generation sequencing to cancer specimens in resource-rich regions has identified new molecular mechanisms. However, such molecular testing has generally not been applied to tumors from SSA where the aggressive nature and younger age of women with breast cancer argues for the potential for novel pathogenic mechanisms. Here, we describe the somatic mutation profile of breast cancer in Uganda. Methods: We enrolled 100 consecutive women with a new diagnosis of invasive breast cancer at the Uganda Cancer Institute (UCI) in Kampala - the primary cancer center of Uganda and neighboring countries. Histopathologic classification was performed at the UCI and revaluated in a blinded fashion at the Fred Hutchinson Cancer Center (Seattle, WA). Demographic and clinical data were obtained. A biopsy specimen of the tumor tissue was obtained, snap frozen, processed using standard protocols to obtain DNA, and sequenced using the clinically-validated UW-OncoPlex assay, identifying all classes of variants and mutations. Results: We analyzed data from 100 women with a histologically-confirmed diagnosis of breast cancer between the ages of 35 and 65 - the vast majority of whom presented with either stage 3 or stage 4 (92%). All 100 tumor specimens were successfully sequenced, with, 96 (96%) demonstrating somatic mutations. The most commonly altered gene was TP53, with mutations in 65% of patients, with identified variant classes including truncations (18), missense (19), and copy loss (33). PIK3CA mutations were identified in 36% of patients, while copy gain or amplification were identified in MYC (50%), CCND1 (31%), FGFR1 (26%). EGFR (9%), and ERRB2 (24%). Nearly half of the women had either a mutation in BRCA1 (24%) or BRCA2 (24%); 6 (6%) of the tumors expressed mutations in both BRCA1 and BRCA2. Conclusions: We identified a diverse landscape of somatic mutations - the prevalence of BRCA1, BRCA2, and PIK3CA mutations are considerably higher than in other documented populations. A better understanding of the mutational profile can provide biological insights, inform prognosis, and serve as a predictive biomarker. As mutations in BRCA1/2 and PIK3CA can potentially be treated with targeted therapies (e.g. PARP inhibitor, PI3K inhibitor), such data can inform policymakers, allow for inclusion of these therapeutics in the formulary and in the WHO Model List of Essential Medicines, and reduce health disparities. Notably, all cases were successfully sequenced, with 96% of cases demonstrated somatic mutations, even without employing specific enrichment strategies commonly used in high-income countries.