Female breast cancer (BC) is the leading cause of cancer-related deaths worldwide with higher mortality rates and early onset in developing countries. The molecular basis of early disease onset is still elusive. We recruited 472 female breast cancer from two sub-Saharan African countries (Cameroon and Congo) between 2007 and 2018 and collected clinical data from these patients. To investigate the molecular drivers of early disease onset, we analyzed publicly available breast cancer molecular data from the cancer genome atlas (TCGA) and the gene expression omnibus (GEO) for copy number alteration, mutation and gene expression. Early BC onset (EOBRCA) (diagnosis before 45 years) was higher in African women compared with the TCGA cohort (51.7% vs 15.6%). The tumor grade, mitotic index, HER2 + phenotype, basal-like phenotype and ki67 were higher in EOBRCA for all cohorts. BC risk factors such as parity, breastfeeding early onset of menarche and use of hormonal contraceptives were significantly associated with EOBRCA (p < 0.05). EOBRCA was equally associated with copy number alterations in several oncogenes including CDH6 and FOXM1 and tumor suppressor including TGM3 and DMBT1 as well as higher TP53 mutation rates (OR: 2.93, p < 0.01). There was a significant enrichment of TGFß signaling in EOBRCA with TGM3 deletions, which was associated with high expression of all SMAD transcription factors as well as WNT ligands. The Frizzled receptors FZD1, FZD4 and FZD6 were significantly upregulated in EOBRCA, suggesting activation of non-canonical WNT signaling. Our data, suggest the implication of TGM3 deletion in early breast cancer onset. Further molecular investigations are warranted in African patients.

BackgroundFemale breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide and higher mortality rates are observed in developing countries. Data from African Americans women are often used to draw inference in African BC and little is currently known about BC traits in indigenous African (IA) women.MethodsThis study prospectively enrolled 472 female patients with BC from Cameroon and Congo Brazzaville between 2007 and 2018. Patient demographics and clinical phenotypes were documented. Additional BC molecular data was downloaded from the cancer genome atlas (TCGA) and the gene expression omnibus (GEO). Demographic and clinical data from the different IA patient cohorts were analyzed to identify unique BC traits in African women. Molecular data from the TCGA was then analyzed to understand key BC traits identified in IA women.ResultsThe average age at BC diagnosis in IA women was more than 10 years earlier (46.5 ± 12.9) than within the TCGA samples (58.5 ± 13.2). Early onset of BC was observed more in IA women than in the TCGS (51.7% vs 15.6%). There was no difference in mean age at diagnosis between African American and white women. IA women had about 60% of T4 stage tumors compared with less than 5% in the TCGA cohort. Using CNA, mutation and gene expression data from the TCGA, we identified somatic copy number amplifications and upregulation of oncogenes such as CDH6, FOXM1, NAAA and CXCL10 in patients with early onset of BC. Deletion of tumor suppressor with corresponding downregulation was equally observed for TGM3, DMBT1 and MYO18B. TP53 mutations were associated with early BC onset (OR: 2.93, p < 0.01). Amplification and upregulation of the oncogene CDH6, PPP1R9B and SLC1A3 were associated with survival (HR: 0.51, 95% CI; 0.23-1.13, p = 0.096 and HR: 0.36, 95% CI: 0.18-0.68, p = 0.002, and HR: 0.14, 95% CI: 0.03-0.6, p = 0.008, respectively).ConclusionEarly onset of BC in IA women in this study might reflect yet unidentified genomic alterations. Dedicated studies are required to establish the genetic underpinning of BC in IA women to support tailored management strategies