Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

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. We thank Aida Murra, Naheed Shaikh, Justine Korteweg, Jeremy Tai, Eleanor Carlyle, Leonora Conneely, KimEdmonds, Karla Lingard, Karen O'Meara, Helen Breeze, Sarah Sarker, Lesley Cooper, Linda Shephard, Susie Slater, and Catherine Rogers for study support. We thank the patients and their families. S.T. and H.X. are funded by Cancer Research UK (CRUK) (C50947/A18176). S.T., T.C., J.L., and M.G. are funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.I.L. is funded by the Ministerio de Economia y Competitividad (MINECO, SAF2016-79847-R). M.S., A.S., J. Lynch, R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity. K.L. is funded by UK Medical Research Council (MR/P014712/1). T.B.K.W. is funded by the European Union Seventh Framework Programme (FP7-People-2013-ITN). M.J.-H. is funded by the NIHR. N.M.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. N.M.L. is additionally funded by a Wellcome Trust Joint Investigator Award (103760/Z/14/Z) and the MRC eMedLab Medical Bioinformatics Infrastructure Award (MR/L016311/1). M.K. is funded by the Danish Cancer Society grant (R90-A6213). P.C. is funded by the Wellcome Trust (WT088340MA). N.M. receives funding from CRUK, Rosetrees, and the NIHR BRC at University College London Hospitals. C.S. is a Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (THESEUS), Marie Curie Network PloidyNet, the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. C.S., O.P., D.R., I.C., and Z.S. are funded by NovoNordisk Foundation (16584). O.P., D.R., and I.C. are funded by the National Research, Development and Innovation Office of Hungary (NVKP_16-1-20160004). This work was supported by CRUK (Clinical Scientist Fellowship to S.T., C50947/A18176), The Francis Crick Institute, which receives its core funding from Cancer Reseach UK (FC010110), the UK Medical Research Council (FC010110), the Wellcome Trust (FC010110), and NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (A109). High-performance computing was supported by eMedLab. The results published here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.