Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Cell. 2018 Apr 12 [Epub]

Thomas J Mitchell, Samra Turajlic, Andrew Rowan, David Nicol, James H R Farmery, Tim O'Brien, Inigo Martincorena, Patrick Tarpey, Nicos Angelopoulos, Lucy R Yates, Adam P Butler, Keiran Raine, Grant D Stewart, Ben Challacombe, Archana Fernando, Jose I Lopez, Steve Hazell, Ashish Chandra, Simon Chowdhury, Sarah Rudman, Aspasia Soultati, Gordon Stamp, Nicos Fotiadis, Lisa Pickering, Lewis Au, Lavinia Spain, Joanna Lynch, Mark Stares, Jon Teague, Francesco Maura, David C Wedge, Stuart Horswell, Tim Chambers, Kevin Litchfield, Hang Xu, Aengus Stewart, Reza Elaidi, Stéphane Oudard, Nicholas McGranahan, Istvan Csabai, Martin Gore, P Andrew Futreal, James Larkin, Andy G Lynch, Zoltan Szallasi, Charles Swanton, Peter J Campbell, TRACERx Renal Consortium

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Academic Urology Group, Department of Surgery, Addenbrooke's Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK., Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK; Renal and Skin Units, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK., Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK., Renal and Skin Units, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK., CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK., Guy's and St Thomas' National Health Service (NHS) Foundation Trust, Great Maze Pond, London SE1 9RT, UK., Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK., Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Renal and Skin Units, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK., Academic Urology Group, Department of Surgery, Addenbrooke's Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK., Department of Pathology, Cruces University Hospital, Biocruces Institute, University of the Basque Country (UPV/EHU), Barakaldo, Spain., Experimental Histopathology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Interventional Radiology Department, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK., Big Data Institute, University of Oxford, Old Road Campus, Oxford OX3 7FZ, UK., Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Hôpital Européen Georges Pompidou 20, rue Leblanc, 75908 Paris, France., Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK., Department of Physics of Complex Systems, Eotvos Lorand University, Budapest, Hungary., The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine, Houston, TX 77030, USA., CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK; School of Medicine, University of St. Andrews, North Haugh, St. Andrews KY16 9TF, UK., Centre for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology (CHIP@HST), Harvard Medical School, Boston, MA, USA., Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Department of Medical Oncology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London NW1 2BU, UK. Electronic address: ., Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK. Electronic address: .