Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Samra Turajlic; Hang Xu; Kevin Litchfield; Andrew Rowan; Stuart Horswell; Tim Chambers; Tim O'Brien; Jose I Lopez; 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; Wei Xing; 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 Juul Birkbak; Gareth A Wilson; Dezso Ribli; Orsolya Pipek; Marcin Krzystanek; Istvan Csabai; Zoltan Imre Szallasi; Martin Gore; Nicholas McGranahan; Peter Van Loo; Peter Campbell; James Larkin; Charles Swanton

doi:10.1016/j.cell.2018.03.043

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan, Stuart Horswell, Tim Chambers, Tim O'Brien, Jose I Lopez, 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 ChowdhurySarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Aengus Stewart, Wei Xing, 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 Juul Birkbak, Gareth A Wilson, Dezso Ribli, Orsolya Pipek, Marcin Krzystanek, Istvan Csabai, Zoltan Imre Szallasi, Martin Gore, Nicholas McGranahan, Peter Van Loo, Peter Campbell, James Larkin, Charles Swanton^*

^*Corresponding author for this work

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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.

Original language	English
Article number	e11
Journal	Cell
Volume	173
Issue number	3
Pages (from-to)	595-610
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2018.03.043
Publication status	Published - 2018

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Turajlic, S., Xu, H., Litchfield, K., Rowan, A., Horswell, S., Chambers, T., O'Brien, T., Lopez, J. I., Watkins, T. B. K., Nicol, D., Stares, M., Challacombe, B., Hazell, S., Chandra, A., Mitchell, T. J., Au, L., Eichler-Jonsson, C., Jabbar, F., Soultati, A., ... Swanton, C. (2018). Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell, 173(3), 595-610. Article e11. https://doi.org/10.1016/j.cell.2018.03.043

@article{0283a41ff3c84e43bf37e06dbf418c61,

title = "Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal",

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.",

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

year = "2018",

doi = "10.1016/j.cell.2018.03.043",

language = "English",

volume = "173",

pages = "595--610",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

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Turajlic, S, Xu, H, Litchfield, K, Rowan, A, Horswell, S, Chambers, T, O'Brien, T, Lopez, JI, Watkins, TBK, Nicol, D, Stares, M, Challacombe, B, Hazell, S, Chandra, A, Mitchell, TJ, Au, L, Eichler-Jonsson, C, Jabbar, F, Soultati, A, Chowdhury, S, Rudman, S, Lynch, J, Fernando, A, Stamp, G, Nye, E, Stewart, A, Xing, W, Smith, JC, Escudero, M, Huffman, A, Matthews, N, Elgar, G, Phillimore, B, Costa, M, Begum, S, Ward, S, Salm, M, Boeing, S, Fisher, R, Spain, L, Navas, C, Grönroos, E, Hobor, S, Sharma, S, Aurangzeb, I, Lall, S, Polson, A, Varia, M, Horsfield, C, Fotiadis, N, Pickering, L, Schwarz, RF, Silva, B, Herrero, J, Luscombe, NM, Jamal-Hanjani, M, Rosenthal, R, Birkbak, NJ, Wilson, GA, Ribli, D, Pipek, O, Krzystanek, M, Csabai, I, Szallasi, ZI, Gore, M, McGranahan, N, Van Loo, P, Campbell, P, Larkin, J & Swanton, C 2018, 'Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal', Cell, vol. 173, no. 3, e11, pp. 595-610. https://doi.org/10.1016/j.cell.2018.03.043

TY - JOUR

T1 - Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

AU - Turajlic, Samra

AU - Xu, Hang

AU - Litchfield, Kevin

AU - Rowan, Andrew

AU - Horswell, Stuart

AU - Chambers, Tim

AU - O'Brien, Tim

AU - Lopez, Jose I

AU - Watkins, Thomas B K

AU - Nicol, David

AU - Stares, Mark

AU - Challacombe, Ben

AU - Hazell, Steve

AU - Chandra, Ashish

AU - Mitchell, Thomas J

AU - Au, Lewis

AU - Eichler-Jonsson, Claudia

AU - Jabbar, Faiz

AU - Soultati, Aspasia

AU - Chowdhury, Simon

AU - Rudman, Sarah

AU - Lynch, Joanna

AU - Fernando, Archana

AU - Stamp, Gordon

AU - Nye, Emma

AU - Stewart, Aengus

AU - Xing, Wei

AU - Smith, Jonathan C

AU - Escudero, Mickael

AU - Huffman, Adam

AU - Matthews, Nik

AU - Elgar, Greg

AU - Phillimore, Ben

AU - Costa, Marta

AU - Begum, Sharmin

AU - Ward, Sophia

AU - Salm, Max

AU - Boeing, Stefan

AU - Fisher, Rosalie

AU - Spain, Lavinia

AU - Navas, Carolina

AU - Grönroos, Eva

AU - Hobor, Sebastijan

AU - Sharma, Sarkhara

AU - Aurangzeb, Ismaeel

AU - Lall, Sharanpreet

AU - Polson, Alexander

AU - Varia, Mary

AU - Horsfield, Catherine

AU - Fotiadis, Nicos

AU - Pickering, Lisa

AU - Schwarz, Roland F

AU - Silva, Bruno

AU - Herrero, Javier

AU - Luscombe, Nick M

AU - Jamal-Hanjani, Mariam

AU - Rosenthal, Rachel

AU - Birkbak, Nicolai Juul

AU - Wilson, Gareth A

AU - Ribli, Dezso

AU - Pipek, Orsolya

AU - Krzystanek, Marcin

AU - Csabai, Istvan

AU - Szallasi, Zoltan Imre

AU - Gore, Martin

AU - McGranahan, Nicholas

AU - Van Loo, Peter

AU - Campbell, Peter

AU - Larkin, James

AU - Swanton, Charles

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2018.03.043

DO - 10.1016/j.cell.2018.03.043

M3 - Journal article

C2 - 29656894

SN - 0092-8674

VL - 173

SP - 595

EP - 610

JO - Cell

JF - Cell

IS - 3

M1 - e11

ER -

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Abstract

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