Disease aetiology and progression shape the inter-patient multi-omics profile of clear cell renal carcinoma

Abstract Endogenous and exogenous processes are associated with distinctive molecular marks in somatic tissues, including human tumours. Here, we used integrative multi-omics analyses to infer sources of inter-patient somatic variation within clear cell renal cell carcinomas (ccRCC) and used them to explore how the disease aetiology and progression are reflected in the tumour DNA methylome, transcriptome, and somatic mutation profile. The main source of inter-patient variation within ccRCC tumours was associated with ageing, particularly cellular mitotic age estimated by DNA methylation (epiTOC2), clock-like DNA mutational signatures (SBS1/ID1), and telomere attrition, independent to chronological age. This component was associated with PBRM1 and SETD2 somatic cancer driver mutations, genome instability, tumor stage, grade, and ccRCC patient survival. Pan-cancer analysis supported the similar role of this molecular component in other cancer types. The ccRCC tumour microenvironment was another source of inter-patient variation, including a component associated with BAP1 driver mutations, epigenetic regulation of epithelial-mesenchymal transition genes (i.e., IL20RB, WT1) and patient survival. An additional source of ccRCC inter-patient variation was linked to the epigenetic regulation of the xenobiotic metabolism gene GSTP1. This molecular component was associated with tobacco usage and tobacco-related genomic features, implying a relationship with tobacco-related carcinogenesis, but also present in tumours of never-smoking patients, potentially implicating it in other genotoxic effects. By considering how the tumour DNA methylome, transcriptome, and somatic mutation profile vary across patients, we provide novel insights into the endogenous and exogenous processes acting within ccRCC tumours and their relation to the disease aetiology and progression.