Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Samra Turajlic; Hang Xu; Kevin Litchfield; Andrew Rowan; Stuart Horswell; Tim Chambers; Tim O’Brien; José I. López; Thomas B.K. Watkins; David Nicol; Mark Stares; Ben Challacombe; Steve Hazell; Ashish Chandra; Thomas J. Mitchell; Lewis Au; Claudia Eichler-Jonsson; Faiz Jabbar; Aspasia Soultati; Simon Chowdhury; Sarah Rudman; Joanna Lynch; Archana Fernando; Gordon Stamp; Emma Nye; Aengus Stewart; Xing Wei; Jonathan C. Smith; Mickael Escudero; Adam Huffman; Nik Matthews; Greg Elgar; Ben Phillimore; Marta Costa; Sharmin Begum; Sophia Ward; Max Salm; Stefan Boeing; Rosalie Fisher; Lavinia Spain; Carolina Navas; Eva Grönroos; Sebastijan Hobor; Sarkhara Sharma; Ismaeel Aurangzeb; Sharanpreet Lall; Alexander Polson; Mary Varia; Catherine Horsfield; Nicos Fotiadis; Lisa Pickering; Roland F. Schwarz; Bruno Silva; Javier Herrero; Nick M. Luscombe; Mariam Jamal‐Hanjani; Rachel Rosenthal; Nicolai J. Birkbak; Gareth A. Wilson; Orsolya Pipek; Dezső Ribli; Marcin Krzystanek; István Csabai; Zoltán Szállási; Martin Gore; Nicholas McGranahan; Peter Van Loo; Peter J. Campbell; James Larkin; Charles Swanton

doi:10.1016/j.cell.2018.03.043

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Samra Turajlic(Royal Marsden NHS Foundation Trust), Hang Xu(The Francis Crick Institute), Kevin Litchfield(The Francis Crick Institute), Andrew Rowan(The Francis Crick Institute), Stuart Horswell(The Francis Crick Institute), Tim Chambers(The Francis Crick Institute), Tim O’Brien(Guy's and St Thomas' NHS Foundation Trust), José I. López(University of the Basque Country), Thomas B.K. Watkins(The Francis Crick Institute), David Nicol(Royal Marsden NHS Foundation Trust), Mark Stares(The Francis Crick Institute), Ben Challacombe(Guy's and St Thomas' NHS Foundation Trust), Steve Hazell(Royal Marsden NHS Foundation Trust), Ashish Chandra(Guy's and St Thomas' NHS Foundation Trust), Thomas J. Mitchell(Cambridge University Hospitals NHS Foundation Trust), Lewis Au(Royal Marsden NHS Foundation Trust), Claudia Eichler-Jonsson(The Francis Crick Institute), Faiz Jabbar(The Francis Crick Institute), Aspasia Soultati(Guy's and St Thomas' NHS Foundation Trust), Simon Chowdhury(Guy's and St Thomas' NHS Foundation Trust), Sarah Rudman(Guy's and St Thomas' NHS Foundation Trust), Joanna Lynch(Royal Marsden NHS Foundation Trust), Archana Fernando(Guy's and St Thomas' NHS Foundation Trust), Gordon Stamp(The Francis Crick Institute), Emma Nye(The Francis Crick Institute), Aengus Stewart(The Francis Crick Institute), Xing Wei(The Francis Crick Institute), Jonathan C. Smith(The Francis Crick Institute), Mickael Escudero(The Francis Crick Institute), Adam Huffman(The Francis Crick Institute), Nik Matthews(The Francis Crick Institute), Greg Elgar(The Francis Crick Institute), Ben Phillimore(The Francis Crick Institute), Marta Costa(The Francis Crick Institute), Sharmin Begum(The Francis Crick Institute), Sophia Ward(The Francis Crick Institute), Max Salm(The Francis Crick Institute), Stefan Boeing(The Francis Crick Institute), Rosalie Fisher(The Francis Crick Institute), Lavinia Spain(Royal Marsden NHS Foundation Trust), Carolina Navas(The Francis Crick Institute), Eva Grönroos(The Francis Crick Institute), Sebastijan Hobor(The Francis Crick Institute), Sarkhara Sharma(The Francis Crick Institute), Ismaeel Aurangzeb(The Francis Crick Institute), Sharanpreet Lall(Guy's and St Thomas' NHS Foundation Trust), Alexander Polson(Guy's and St Thomas' NHS Foundation Trust), Mary Varia(Guy's and St Thomas' NHS Foundation Trust), Catherine Horsfield(Guy's and St Thomas' NHS Foundation Trust), Nicos Fotiadis(Royal Marsden NHS Foundation Trust), Lisa Pickering(Royal Marsden NHS Foundation Trust), Roland F. Schwarz(Max Delbrück Center), Bruno Silva(The Francis Crick Institute), Javier Herrero(University College London), Nick M. Luscombe(The Francis Crick Institute), Mariam Jamal‐Hanjani(Cancer Research UK), Rachel Rosenthal(Cancer Research UK), Nicolai J. Birkbak(The Francis Crick Institute), Gareth A. Wilson(The Francis Crick Institute), Orsolya Pipek(Eötvös Loránd University), Dezső Ribli(Eötvös Loránd University), Marcin Krzystanek(Technical University of Denmark), István Csabai(Eötvös Loránd University), Zoltán Szállási(Boston Children's Hospital), Martin Gore(Royal Marsden NHS Foundation Trust), Nicholas McGranahan(Cancer Research UK), Peter Van Loo(The Francis Crick Institute), Peter J. Campbell(Wellcome Sanger Institute), James Larkin(Royal Marsden NHS Foundation Trust), Charles Swanton(The Francis Crick Institute)

Cell

April 1, 2018

10.1016/j.cell.2018.03.043

Cited by 669Open Access

Full Text

Abstract

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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