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.

Original publication

DOI

10.1016/j.cell.2018.02.020

Type

Journal article

Journal

Cell

Publication Date

04/04/2018

Volume

173

Pages

611 - 623.e17

Addresses

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Academic Urology Group, Department of Surgery, Addenbrooke's Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK.

Keywords

TRACERx Renal Consortium