IARC 60th Anniversary - 19-21 May 2026
Session : Breast Cancer Etiology: New Findings on Lifestyle, Environmental, and Biological Factors
Dual-approach to shed light on Sub-Saharan African triple-negative breast cancer: patient exomes and high-throughput in vitro models
PINTO R. 1,2,3, MAGALHÃES A. 1,2, ROSÁRIO F. 1,2, FERREIRA D. 4, SALAMANCA P. 5, MIGUEL F. 5, BORGES P. 6, BARBOSA C. 6, COSTA V. 6, LOPES C. 7, GONÇALVES E. 8,12, LARA SANTOS L. 4,9,10,11, PEREIRA L. 1,2
1 Institute for Research and Innovation in Health - i3S, Porto, Portugal; 2 IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; 3 ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal; 4 Research Center of IPO-Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.CCC) Raquel Seruca, Porto, Portugal; 5 Angolan Institute Against Cancer, Luanda, Angola; 6 Hospital Universitário Agostinho Neto, Praia, Cabo Verde; 7 Unilabs | Laboratório Anatomia Patológica, Porto, Portugal; 8 Instituto Superior Técnico (IST), Universidade de Lisboa, Lisboa, Portugal; 9 FP-I3ID, University Fernando Pessoa, Porto, Portugal; 10 Department of Surgical Oncology, Portuguese Oncology Institute of Porto, Porto, Portugal; 11 School of Medicine and Biomedical Sciences, University Fernando Pessoa, Gondomar, Portugal; 12 INESC-ID, Lisboa, Portugal
Background: Omics comparisons between ancestries can reveal useful insights on essential cancer pathways, and may explain heterogeneity in incidence rates, such as the higher prevalence of the most aggressive breast cancer subtype triple-negative breast cancer (TNBC) in women of Sub-Saharan African (SSA) ancestry.
Objectives: To address the critical knowledge gap in TNBC for SSA ancestry, we examined the impact of ancestry using two complementary approaches: contributing for the somatic catalogue of TNBC in SSA tumour samples; and analysing ancestry differences in terms of gene essentiality and drug susceptibility in in vitro cancer cell line (CCL) models.
Methods: We performed whole-exome sequencing (WES), including analysis of 5' and 3' untranslated regions (UTRs), on 30 TNBC samples from Angola and Cape Verde (African cohort). These data were compared against WES data from African- and European-American TNBC cohorts available through The Cancer Genome Atlas. We also mined publicly available high-throughput gene essentiality and drug sensitivity datasets, comparing SSA and European (EUR) TNBC CCLs by applying statistical linear models. The results for the most promising drug were replicated by us and deeply characterized by transcriptomics.
Results: The WES profiling revealed a high somatic mutation burden of the African cohort analysed here, with 86% of variants unreported in the COSMIC database. A total of 17% variants were estimated as having functional coding impact and 20% overlap with cis-regulatory elements. Driver hits were mapped in 25 of 30 patients, involving impactful mutations and CNVs (mainly gains in 1q, 8q, 6, and 10p) in known BC driver genes, which are integral components of response to radiation and related DNA repair pathways. Evidence indicates TTN, CEACAM7, DEFB132, COPZ2 and GAS1 as putative novel driver genes in the TNBC SSA context. Independently, mining public datasets revealed that the gene BLM (a DNA helicase) has a significantly higher essentiality in SSA versus EUR TNBC CCLs. Accordingly, enrichment analyses of gene essentiality identified DNA repair and ubiquitination/neddylation mechanisms as the top hits for the SSA ancestry. SSA TNBC CCLs were also significantly more sensitive to the drug Pevonedistat (a neddylation inhibitor) than the EUR ones. An in vitro drug assay conducted by us allowed to confirm that Pevonedistat leads to a significant decrease in the expression of DNA damage repair/helicase-related pathways, in several of which BLM is a significant core gene.
Conclusions: The global results highlight the added value of conducting omics analyses on SSA populations. Evidence from both approaches converges on the significance of specific DNA damage repair pathways in the TNBC SSA background, with a clear indication of potential therapeutics to be explored in TNBC treatment in Africa and its diaspora.