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

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.

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Item Type:	Article
Authors/Creators:	Culliford, R. https://orcid.org/0000-0003-4534-9241 Lawrence, S.E.D. Mills, C. https://orcid.org/0000-0002-4755-7549 Tippu, Z. Chubb, D. Cornish, A.J. https://orcid.org/0000-0002-3966-3501 Browning, L. Kinnersley, B. https://orcid.org/0000-0003-1783-6296 Bentham, R. Sud, A. https://orcid.org/0000-0002-6133-0164 Pallikonda, H. https://orcid.org/0000-0003-4472-2067 Afshar, M. Akala, O. Brown, J. https://orcid.org/0000-0003-4960-3032 Faust, G. Fife, K. Foy, V. Germanou, S. Giles, M. Grieco, C. Grummet, S. Jain, A. Kanwar, A. Protheroe, A. Raza, I. Rehan, A. Rudman, S. Santiapillai, J. Sarwar, N. Seeva, P. Strong, A. Toki, M. Tran, M. Tutika, R. Waddell, T. Wheater, M. Frangou, A. https://orcid.org/0000-0001-6990-2756 Gruber, A.J. https://orcid.org/0000-0001-7664-4257 Litchfield, K. https://orcid.org/0000-0002-3725-0914 Wedge, D. https://orcid.org/0000-0002-7572-3196 Larkin, J. Turajlic, S. https://orcid.org/0000-0001-8846-136X Houlston, R.S. https://orcid.org/0000-0002-5268-0242
Copyright, Publisher and Additional Information:	© 2024 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Whole Genome Sequencing; Mutation; Von Hippel-Lindau Tumor Suppressor Protein; Prognosis; Male; Female; DNA Copy Number Variations; Middle Aged; Epigenesis, Genetic; Aged; Gene Expression Regulation, Neoplastic; Immunotherapy
Dates:	Published: 15 July 2024 Published (online): 15 July 2024 Accepted: 17 June 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	11 Oct 2024 16:01
Last Modified:	11 Oct 2024 16:01
Published Version:	http://dx.doi.org/10.1038/s41467-024-49692-1
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-024-49692-1
Related URLs:	PubMed URL
Sustainable Development Goals:
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:218310

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

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