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Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

Mitchell, Thomas J and Turajlic, Samra and Rowan, Andrew and Nicol, David and Farmery, James HR and Brien, Tim O and Martincorena, Inigo and Tarpey, Patrick and Angelopoulos, textbfNicos and Yates, Lucy R and Butler, Adam P and Raine, Keiran and Stewart, Grant D and Challacombe, Ben and Fernando, Archana and Lopez, Jose I and Hazell, Steve and Chandra, Ashish and Chowdhury, Simon and Rudman, Sarah and Soultati, Aspasia and Stamp, Gordon and Fotiadis, Nicos and Pickering, Lisa and Au, Lewis and Spain, Lavinia and Lynch, Joanna and Stares, Mark and Teague, Jon and Maura, Francesco and Wedge, David C and Horswell, Stuart and Chambers, Tim and Litchfield, Kevin and Xu, Hang and Stewart, Aengus and Elaidi, Reza and Oudard, Stéphane and McGranahan, Nicholas and Csabai, Istvan and Gore, Martin and Futreal, P Andrew and Larkin, James and Lynch, Andy G and Szallasi, Zoltan and Swanton, Charles and Campbell, Peter J (2018) 'Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.' Cell, 173. 611 - 623. ISSN 0092-8674

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Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Item Type: Article
Uncontrolled Keywords: clear cell renal cell carcinoma, cancer evolution, chromothripsis, Bayesian modeling of evolution
Divisions: Faculty of Science and Health > Computer Science and Electronic Engineering, School of
Depositing User: Elements
Date Deposited: 23 Apr 2020 16:40
Last Modified: 23 Apr 2020 17:15
URI: http://repository.essex.ac.uk/id/eprint/26772

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