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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.

SUBMITTER: Turajlic S 

PROVIDER: S-EPMC5938372 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

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

Cell 20180412 3

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 determinist  ...[more]

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