Transcriptomic and in-silico characterization of ethnic differences in breast cancer

Breast cancer is a global healthcare burden, with growing rates all over the world and heterogeneous presentation, which affects prognosis and survival. It can be classified according to oestrogen, progesterone and HER2 receptor status into ER+/PR+ breast cancer, HER2+ breast cancer and triple negative breast cancer, which present the most aggressive phenotype. Ethnic differences are present in breast cancer incidence, mortality and biological signatures such as polymorphisms frequency, gene expression, DNA methylation and immune infiltrate. The aim of my project was to characterize the genetic and molecular signatures in breast cancer from patients of different ethnicities, particularly regarding gene expression. We performed in silico analysis on public datasets and RNAseq was applied in a cohort of 12 TNBC European patients, and 2 HER2 + breast cancer, 7 luminal A and 4 luminal B breast tumours, belonging to different ethnicities. On the TCGA cohort, we identified transcriptomic and mutational differences. Different distribution of breast cancer subtypes across ethnicities was confirmed, with HER2+ subtype being more common in Asian patients and basal subtype in African patients. Differential expression analysis between ethnicities was then performed, revealing lower levels of cell adhesion molecules in Black patients, while Asian patients presented higher expression of genes of the ErbB pathway in the basal subtype. In the HER2+ subtype and in the luminal A subtype, White patients present an enrichment in several metabolic pathways compared to other ethnicities. Among differentially expressed genes, some of them impacted on overall survival: these include CXCL6 and CXCL8, CLCA2, SCN1A KCNK3, KCNIP3 ion channels and SLC30A10 transporter, and some lncRNAs. Caucasian patients’ enrichment of genes involved in metabolic pathways compared to other ethnicities and KCNIP3 higher expression in African patients were confirmed through RNAseq experiments. Differential expression analysis between basal and other subtypes revealed enrichment in IL-17, cell cycle, Wnt signalling pathway, and stemness, and downregulation of tight junctions, drug metabolism and chemical carcinogenesis, while comparison with healthy tissue revealed enrichment in cell cycle and neutrophil trap formation, and downregulation of antigen processing and presentation, MHC II protein complex and cell adhesion molecules compared to healthy mammary tissue. RNA sequencing on TNBC samples identified several novel lncRNAs, which presented a correlation with genes involved in inflammation and various types of breast cancer and with distant metastasis and progression free survival. In conclusion, we identified several differences in the transcriptomic profile of breast tumours from patients of different ethnicities, spanning from immune response, chemokine expression to ion channels to non-protein coding genes. Pathways enriched in Black patients, which have the most aggressive breast cancer, were often also enriched in TNBC compared to other subtypes or healthy tissue, highlighting their importance in cancer aggressivity and bad prognosis. Ion channels and transporters and lncRNAs demonstrated to be key genes for the characterization of breast cancer biology.