Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

• Keywords
• Cancer Biology, Genomic Epidemiology, Integrative Multi-omics Analysis, Kidney Cancer, Tumour Microenvironment,
• MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• Epigenesis, Genetic MeSH
• Epithelial-Mesenchymal Transition * genetics   MeSH
• Glutathione S-Transferase pi genetics   metabolism   MeSH
• Histone-Lysine N-Methyltransferase genetics   metabolism   MeSH
• Carcinogenesis * genetics   MeSH
• Humans MeSH
• DNA Methylation * MeSH
• Multiomics MeSH
• Mutation * MeSH
• Tumor Suppressor Proteins genetics   metabolism   MeSH
• Kidney Neoplasms * genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aging genetics   MeSH
• Ubiquitin Thiolesterase MeSH
• Transcription Factors genetics   metabolism   MeSH
• Transcriptome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BAP1 protein, human MeSH Browser
• DNA-Binding Proteins MeSH
• Glutathione S-Transferase pi MeSH
• GSTP1 protein, human MeSH Browser
• Histone-Lysine N-Methyltransferase MeSH
• Tumor Suppressor Proteins MeSH
• PBRM1 protein, human MeSH Browser
• SETD2 protein, human MeSH Browser
• Ubiquitin Thiolesterase MeSH
• Transcription Factors MeSH