Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

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.

Zoltan Szallasi | Ashish Chandra | Adam Huffman | Charles Swanton | Simon Chowdhury | Ben Challacombe | Roland F. Schwarz | Peter Campbell | Dezso Ribli | Mariam Jamal-Hanjani | Marcin Krzystanek | Kevin Litchfield | Samra Turajlic | Peter Van Loo | Istvan Csabai | Nicolai J. Birkbak | Nicholas McGranahan | Rachel Rosenthal | Thomas B.K. Watkins | Gareth A. Wilson | David Nicol | Thomas J. Mitchell | Z. Szallasi | I. Csabai | N. Luscombe | P. Campbell | P. Van Loo | R. Schwarz | S. Horswell | M. Salm | R. Fisher | N. McGranahan | B. Phillimore | Sharmin Begum | G. Stamp | L. Pickering | M. Gore | S. Hazell | A. Stewart | C. Swanton | Claudia Eichler-Jonsson | B. Challacombe | G. Wilson | R. Rosenthal | M. Jamal-Hanjani | O. Pipek | M. Stares | N. Birkbak | J. Herrero | G. Elgar | S. Hobor | J. Larkin | T. Mitchell | S. Rudman | S. Chowdhury | T. Watkins | S. Turajlic | Sophia Ward | E. Grönroos | T. Chambers | Nik Matthews | Hang Xu | K. Litchfield | A. Rowan | T. O'brien | J. López | D. Nicol | A. Chandra | L. Au | F. Jabbar | A. Soultati | Joanna Lynch | A. Fernando | E. Nye | Wei Xing | Jonathan C. Smith | Mickael Escudero | A. Huffman | Marta Costa | S. Boeing | L. Spain | C. Navas | Sarkhara Sharma | I. Aurangzeb | S. Lall | A. Polson | M. Varia | C. Horsfield | N. Fotiadis | Bruno Silva | D. Ribli | M. Krzystanek | Martin Gore | Nicos Fotiadis | Sebastijan Hobor | Andrew Rowan | Mark Stares | Emma Nye | Greg Elgar | James Larkin | Sophia Ward | Eva Grönroos | Tim Chambers | Nik Matthews | Javier Herrero | Aengus Stewart | Hang Xu | Stuart Horswell | Tim O’Brien | Jose I. Lopez | Steve Hazell | Lewis Au | Claudia Eichler-Jonsson | Faiz Jabbar | Aspasia Soultati | Sarah Rudman | Joanna Lynch | Archana Fernando | Gordon Stamp | Wei Xing | Mickael Escudero | Ben Phillimore | Marta Costa | Sharmin Begum | Max Salm | Stefan Boeing | Rosalie Fisher | Lavinia Spain | Carolina Navas | Sarkhara Sharma | Ismaeel Aurangzeb | Sharanpreet Lall | Alexander Polson | Mary Varia | Catherine Horsfield | Lisa Pickering | Bruno Silva | Nick M. Luscombe | Orsolya Pipek | O. Pipek | N. Mcgranahan | M. Escudero | S. Ward | G. Wilson | Javier Herrero | Mark Stares

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