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

Mitchell, TJ; Turajlic, S; Rowan, A; Nicol, D; Farmery, JHR; O'Brien, T; Martincorena, I; ... Campbell, PJ; + view all (2018) Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal. Cell , 173 (3) , Article e17. 10.1016/j.cell.2018.02.020. Green open access

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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.

Type: Article
Title: Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cell.2018.02.020
Publisher version: http://doi.org/10.1016/j.cell.2018.02.020
Language: English
Additional information: Crown Copyright © 2018 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: clear cell renal cell carcinoma, cancer evolution, chromothripsis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10050901
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