Disease aetiology and progression shape the inter-patient multi-omics profile of clear cell renal carcinoma
Year: 2024
Type: preprint
Study design: Observational Study
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.
Source: Research Square
Authors: Ricardo Cortez Cardoso Penha, Alexandra Sexton-Oates, Sergey Senkin, Hanla A. Park, Joshua Atkins, Ivana Holcatova, Anna Hornakova, Slavisa Savic, Simona Ognjanovic, Beata Świątkowska, Jolanta Lissowska, David Zaridze, Anush Mukeria, Vladimir Janout, Amelie Chabrier, Vincent Cahais, Cyrille Cuenin, Ghislaine Scelo, Matthieu Foll, Zdenko Herceg, Paul Brennan, Karl Smith-Byrne, Nicolas Alcala, James D. McKay
Institutions: Centre international de recherche sur le cancer, World Health Organization, University of Oxford, Charles University, Nofer Institute of Occupational Medicine, The Maria Sklodowska-Curie National Research Institute of Oncology, Russian Cancer Research Center NN Blokhin, Palacký University Olomouc
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4391773520