Timing the landmark events in the evolution of clear cell renal cell cancer : TRACERx renal
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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.
Mitchell , T J , Turajlic , S , Rowan , A , Nicol , D , Farmery , J H R , O’Brien , T , Martincorena , I , Tarpey , P , Angelopoulos , N , Yates , L R , Butler , A P , Raine , K , Stewart , G D , Challacombe , B , Fernando , A , Lopez , J I , Hazell , S , Chandra , A , Chowdhury , S , Rudman , S , Soultati , A , Stamp , G , Fotiadis , N , Pickering , L , Au , L , Spain , L , Lynch , J , Stares , M , Teague , J , Maura , F , Wedge , D C , Horswell , S , Chambers , T , Litchfield , K , Xu , H , Stewart , A , Elaidi , R , Oudard , S , McGranahan , N , Csabai , I , Gore , M , Futreal , P A , Larkin , J , Lynch , A G , Szallasi , Z , Swanton , C & Campbell , P J 2018 , ' Timing the landmark events in the evolution of clear cell renal cell cancer : TRACERx renal ' Cell , vol In press . DOI: 10.1016/j.cell.2018.02.020
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/).
DescriptionThe work presented in this manuscript was funded by EU FP7 (project PREDICT ID number 259303) and the Wellcome Trust and Cancer Research UK. S.T. is funded by Cancer Research UK (C50947/A18176). S.T., J.L., and M.G. receive funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.H.R.F. and A.G.L. were supported by the University of Cambridge, Cancer Research UK (C14303/A17197), and Hutchison Whampoa. K.L. is supported by a UK Medical Research Council Skills Development Fellowship Award. C.S. is funded by Cancer Research UK (TRACERx), the Rosetrees Trust, NovoNordisk Foundation (16584), EU FP7 (projects PREDICT and RESPONSIFY, ID number 259303), the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council (THESEUS), and National Institute for Health Research University College London Hospitals Biomedical Research Centre. P.J.C. has a Wellcome Trust Senior Clinical Research Fellowship (WT088340MA).
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