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Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach
Ricardo Cortez Cardoso Penha1, Alexandra Sexton Oates1, Sergey Senkin1
1Genomic Epidemiology branch, International Agency for Research on Cancer/World Health Organization (IARC/WHO), Lyon, 69366, France.
Abstract:
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.
Insights
This study links aging, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney cancer development. These factors influence tumor progression and patient survival, offering insights into broader cancer mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer development involves complex biological mechanisms leaving molecular signatures.
- Multi-omics and epidemiological data can reveal hidden relationships in carcinogenesis.
Purpose of the Study:
- To integrate DNA methylome, transcriptome, and somatic mutation data in kidney tumors.
- To uncover links between aging, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism in kidney carcinogenesis.
- To explore these relationships across multiple cancer types.
Main Methods:
- Integrative analysis of multi-omics data (DNA methylome, transcriptome, somatic mutations).
- Association studies linking molecular profiles with clinical and epidemiological factors.
- Pan-cancer analysis to identify conserved relationships.
Main Results:
- Ageing, EMT, and xenobiotic metabolism are linked to kidney carcinogenesis.
- Specific molecular markers (epiTOC2, SBS1, telomere length, PBRM1/SETD2 mutations) indicate accelerated aging in tumors.
- BAP1 mutations correlate with EMT gene upregulation, immune infiltration, advanced stage, and poorer survival.
- GSTP1 silencing interacts with tobacco use, suggesting genotoxic effects.
Conclusions:
- The study enhances understanding of kidney cancer development, risk factors, and progression.
- Identified molecular fingerprints provide insights into carcinogenesis.
- Findings have implications for understanding and potentially treating other cancer types.
