Journal
CELL
Volume 173, Issue 3, Pages 611-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.02.020
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Funding
- EU FP7 (project PREDICT) [259303]
- Wellcome Trust
- Cancer Research UK
- Cancer Research UK [C50947/A18176]
- National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research [A109]
- University of Cambridge, Cancer Research UK [C14303/A17197]
- Hutchison Whampoa
- UK Medical Research Council Skills Development Fellowship Award
- Cancer Research UK (TRACERx)
- Rosetrees Trust
- NovoNordisk Foundation [16584]
- EU FP7 [259303]
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- European Research Council (THESEUS)
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Wellcome Trust Senior Clinical Research Fellowship [WT088340MA]
- MRC [MR/P014712/1] Funding Source: UKRI
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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 50 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.
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