Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma

Richard Culliford, Samuel E. D. Lawrence, Charlie Mills, Zayd Tippu, Daniel Chubb, Alex J. Cornish, Lisa Browning, Ben Kinnersley, Robert Bentham, Amit Sud, Husayn Pallikonda, Anna Frangou, Andreas J. Gruber, Kevin Litchfield, David Wedge, James Larkin, Samra Turajlic and Richard S. Houlston ()
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Richard Culliford: The Institute of Cancer Research
Samuel E. D. Lawrence: The Institute of Cancer Research
Charlie Mills: The Institute of Cancer Research
Zayd Tippu: The Royal Marsden NHS Foundation Trust
Daniel Chubb: The Institute of Cancer Research
Alex J. Cornish: The Institute of Cancer Research
Lisa Browning: Oxford University Hospitals NHS Foundation Trust
Ben Kinnersley: The Institute of Cancer Research
Robert Bentham: University College London Cancer Institute
Amit Sud: The Institute of Cancer Research
Husayn Pallikonda: The Royal Marsden NHS Foundation Trust
Anna Frangou: University of Oxford
Andreas J. Gruber: University of Konstanz
Kevin Litchfield: University College London Cancer Institute
David Wedge: University of Manchester
James Larkin: The Royal Marsden NHS Foundation Trust
Samra Turajlic: The Royal Marsden NHS Foundation Trust
Richard S. Houlston: The Institute of Cancer Research

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

Date: 2024
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DOI: 10.1038/s41467-024-49692-1

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