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

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

doi:10.1016/j.cell.2018.02.020

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

Cell. 2018 Apr 19;173(3):611-623.e17. doi: 10.1016/j.cell.2018.02.020. Epub 2018 Apr 12.

Authors

Thomas J Mitchell¹, Samra Turajlic², Andrew Rowan³, David Nicol⁴, James H R Farmery⁵, Tim O'Brien⁶, Inigo Martincorena⁷, Patrick Tarpey⁷, Nicos Angelopoulos⁷, Lucy R Yates⁸, Adam P Butler⁷, Keiran Raine⁷, Grant D Stewart⁹, Ben Challacombe⁶, Archana Fernando⁶, Jose I Lopez¹⁰, Steve Hazell³, Ashish Chandra⁶, Simon Chowdhury⁶, Sarah Rudman⁶, Aspasia Soultati⁶, Gordon Stamp¹¹, Nicos Fotiadis¹², Lisa Pickering⁴, Lewis Au⁴, Lavinia Spain⁴, Joanna Lynch⁴, Mark Stares⁴, Jon Teague⁷, Francesco Maura⁷, David C Wedge¹³, Stuart Horswell¹⁴, Tim Chambers³, Kevin Litchfield³, Hang Xu³, Aengus Stewart¹⁴, Reza Elaidi¹⁵, Stéphane Oudard¹⁵, Nicholas McGranahan¹⁶, Istvan Csabai¹⁷, Martin Gore⁴, P Andrew Futreal¹⁸, James Larkin⁴, Andy G Lynch¹⁹, Zoltan Szallasi²⁰, Charles Swanton²¹, Peter J Campbell²²; TRACERx Renal Consortium

Affiliations

¹ 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.
² 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.
³ Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
⁴ Renal and Skin Units, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK.
⁵ CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
⁶ Guy's and St Thomas' National Health Service (NHS) Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
⁷ Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
⁸ 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.
⁹ Academic Urology Group, Department of Surgery, Addenbrooke's Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK.
¹⁰ Department of Pathology, Cruces University Hospital, Biocruces Institute, University of the Basque Country (UPV/EHU), Barakaldo, Spain.
¹¹ Experimental Histopathology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
¹² Interventional Radiology Department, The Royal Marsden National Health Service (NHS) Foundation Trust, London SW3 6JJ, UK.
¹³ Big Data Institute, University of Oxford, Old Road Campus, Oxford OX3 7FZ, UK.
¹⁴ Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
¹⁵ Hôpital Européen Georges Pompidou 20, rue Leblanc, 75908 Paris, France.
¹⁶ 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.
¹⁷ Department of Physics of Complex Systems, Eotvos Lorand University, Budapest, Hungary.
¹⁸ The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine, Houston, TX 77030, USA.
¹⁹ 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.
²⁰ 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.
²¹ 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: [email protected].
²² Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK. Electronic address: [email protected].

Abstract

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.

Keywords: cancer evolution; chromothripsis; clear cell renal cell carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions
Adult
Aged
Aged, 80 and over
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / pathology*
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 5
Disease Progression*
Female
Gene Dosage
Genome, Human
Humans
Kidney Neoplasms / genetics*
Kidney Neoplasms / pathology*
Male
Middle Aged
Mutation*
Prospective Studies
Telomerase / genetics
Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

5' Untranslated Regions
Von Hippel-Lindau Tumor Suppressor Protein
TERT protein, human
Telomerase
VHL protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding