Journal
CELL
Volume 173, Issue 3, Pages 595-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.03.043
Keywords
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Categories
Funding
- Cancer Research UK (CRUK) [C50947/A18176]
- National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research [A109]
- Ministerio de Economia y Competitividad (MINECO) [SAF2016-79847-R]
- Royal Marsden Cancer Charity
- UK Medical Research Council [MR/P014712/1, FC010110]
- European Union Seventh Framework Programme (FP7-People-ITN)
- NIHR
- Wellcome Trust Joint Investigator Award [103760/Z/14/Z]
- MRC eMedLab Medical Bioinformatics Infrastructure Award [MR/L016311/1]
- Danish Cancer Society grant [R90-A6213]
- Wellcome Trust [FC010110, WT088340MA]
- CRUK
- Rosetrees
- NIHR BRC at University College London Hospitals
- Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network)
- CRUK Lung Cancer Centre of Excellence
- Stand Up 2 Cancer (SU2C)
- Rosetrees and Stoneygate Trusts
- NovoNordisk Foundation (THESEUS)
- Marie Curie Network PloidyNet
- CRUK University College London Experimental Cancer Medicine Centre
- NovoNordisk Foundation [16584]
- National Research, Development and Innovation Office of Hungary [NVKP_16-1-20160004]
- CRUK (Clinical Scientist Fellowship) [C50947/A18176]
- Cancer Reseach UK [FC010110]
- NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research [A109]
- eMedLab
- TCGA Research
- Wellcome Trust [103760/Z/14/Z] Funding Source: Wellcome Trust
- MRC [MR/P014712/1, MR/L016311/1] Funding Source: UKRI
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The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with > 10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
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