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.

Cancer Epidemiology Unit University of Oxford Oxford Oxford OX3 7LF UK

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Łódź 90 950 Poland

Department of Urology Kliničko Bolnički Centar Dr Dragiša Mišović Belgrade Serbia

Epigenomics and Mechanisms Branch International Agency for Research on Cancer World Health Organization Lyon 69366 France

Faculty of Health Sciences Palacký University Olomouc 77900 Olomouc Czechia

Genomic Epidemiology branch International Agency for Research on Cancer World Health Organization Lyon 69366 France

Institute of Hygiene and Epidemiology Charles University Prague 12800 Czechia

Institute of Public Health and Preventive Medicine Charles University Prague 15000 Czechia

International Organization for Cancer Prevention and Research Belgrade 11070 Serbia

Maria Sklodowska Curie National Research Institute of Oncology Warszawa 00 001 Poland

N N Blokhin Cancer Research Center Moscow 115478 Russia

The Observational and Pragmatic Research Institute Midview City 573969 Singapore

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