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Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal

Mitchell, Thomas J., Turajlic, Samra, Rowan, Andrew, Nicol, David, Farmery, James H. R., O'Brien, Tim, Martincorena, Inigo, Tarpey, Patrick, Angelopoulos, Nicos, Yates, Lucy R., Butler, Adam P., Raine, Keiran, Stewart, Grant D., Challacombe, Ben, Fernando, Archana, Lopez, Jose I., Hazell, Steve, Chandra, Ashish, Chowdhury, Simon, Rudman, Sarah, Soultati, Aspasia, Stamp, Gordon, Fotiadis, Nicos, Pickering, Lisa, Au, Lewis, Spain, Lavinia, Lynch, Joanna, Stares, Mark, Teague, Jon, Maura, Francesco, Wedge, David C., Horswell, Stuart, Chambers, Tim, Litchfield, Kevin, Xu, Hang, Stewart, Aengus, Elaidi, Reza, Oudard, Stephane, McGranahan, Nicholas, Csabai, Istvan, Gore, Martin, Futreal, P. Andrew, Larkin, James, Lynch, Andy G., Szallasi, Zoltan, Swanton, Charles and Campbell, Peter J. 2018. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal. Cell 173 (3) , 611-623.e17. 10.1016/j.cell.2018.02.020

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Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, 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
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article under the CC BY license.The TRACERx Renal Consortium
Publisher: Elsevier
ISSN: 0092-8674
Date of First Compliant Deposit: 29 July 2020
Date of Acceptance: 7 February 2018
Last Modified: 10 Feb 2021 17:30
URI: http://orca.cardiff.ac.uk/id/eprint/133804

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