부산대학교 도서관

the TRACERx Renal Consortium Keywords renal cell cancer; cancer evolution; intratumor heterogeneity; metastasis; tumor diversity; deterministic evolution; chromosome instability; punctuated evolution; branched evolution; linear evolution Highlights * ccRCC evolutionary subtypes correlate with clinical phenotypes * Genetic diversity and chromosome complexity contribute to patient outcomes * Early fixation of multiple driver events leads to rapid growth and metastases * Subclonal diversification is linked with slower growth and attenuated metastases Summary 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. Author Affiliation: (1) Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, London NW1 1AT, UK (2) Renal and Skin Units, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK (3) Department of Bioinformatics and Biostatistics, the Francis Crick Institute, London NW1 1AT, UK (4) Urology Centre, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK (5) Department of Pathology, Cruces University Hospital, Biocruces Institute, University of the Basque Country, Barakaldo, Spain (6) Department of Urology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK (7) Department of Pathology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK (8) Department of Pathology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 7EH, UK (9) Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK (10) Department of Surgery, Addenbrooke's Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK (11) Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK (12) Experimental Histopathology Laboratory, the Francis Crick Institute, London NW1 1AT, UK (13) Department of Scientific Computing, the Francis Crick Institute, London NW1 1AT, UK (14) Advanced Sequencing Facility, the Francis Crick Institute, London NW1 1AT, UK (15) Department of Radiology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK (16) Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany (17) Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK (18) Bioinformatics and Computational Biology Laboratory, the Francis Crick Institute, London NW1 1AT, UK (19) Cancer Research UK Lung Cancer Centre of Excellence London, University College London Cancer Institute, London WC1E 6DD, UK (20) Department of Physics of Complex Systems, ELTE Eotvos Lorand University, Budapest, Hungary (21) Department of Bio and Health Informatics, Technical University of Denmark, Kgs Lyngby 2800, Denmark (22) Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA (23) Cancer Genomics Laboratory, the Francis Crick Institute, London NW1 1AT, UK (24) Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium (25) Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK * Corresponding author Article History: Received 15 September 2017; Revised 12 January 2018; Accepted 19 March 2018 (miscellaneous) Published: April 12, 2018 (footnote)26 These authors contributed equally (footnote)27 Lead Contact Byline: Samra Turajlic (1,2,26), Hang Xu (1,26), Kevin Litchfield (1,26), Andrew Rowan (1,26), Stuart Horswell (3,26), Tim Chambers (1,26), Tim O'Brien (4,26), Jose I. Lopez (5,26), Thomas B.K. Watkins (1), David Nicol (6), Mark Stares (1), Ben Challacombe (4), Steve Hazell (7), Ashish Chandra (8), Thomas J. Mitchell (9,10), Lewis Au (2), Claudia Eichler-Jonsson (1), Faiz Jabbar (1), Aspasia Soultati (11), Simon Chowdhury (11), Sarah Rudman (11), Joanna Lynch (2), Archana Fernando (4), Gordon Stamp (12), Emma Nye (12), Aengus Stewart (3), Wei Xing (13), Jonathan C. Smith (13), Mickael Escudero (3), Adam Huffman (13), Nik Matthews (14), Greg Elgar (14), Ben Phillimore (14), Marta Costa (14), Sharmin Begum (14), Sophia Ward (1,14,19), Max Salm (3), Stefan Boeing (3), Rosalie Fisher (1), Lavinia Spain (2), Carolina Navas (1), Eva Gronroos (1), Sebastijan Hobor (1), Sarkhara Sharma (1), Ismaeel Aurangzeb (1), Sharanpreet Lall (11), Alexander Polson (8), Mary Varia (8), Catherine Horsfield (8), Nicos Fotiadis (15), Lisa Pickering (2), Roland F. Schwarz (16), Bruno Silva (13), Javier Herrero (17), Nick M. Luscombe (18), Mariam Jamal-Hanjani (19), Rachel Rosenthal (17,19), Nicolai J. Birkbak (1,19), Gareth A. Wilson (1,19), Orsolya Pipek (20), Dezso Ribli (20), Marcin Krzystanek (21), Istvan Csabai (20), Zoltan Szallasi (21,22), Martin Gore (2), Nicholas McGranahan (19), Peter Van Loo (23,24), Peter Campbell (9), James Larkin [james.larkin@rmh.nhs.uk] (2,*), Charles Swanton [charles.swanton@crick.ac.uk] (1,19,25,27,**)