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

24 Jul 2018

Clear cell renal cell carcinoma 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 cancer. We find hotspots of point mutations in the 5’-UTR of TERT, targeting a MYC-MAX-MAD1 repressor, that result in telomere lengthening. The commonest structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This occurs in childhood or adolescence, is generally the initiating event, and precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited kidney cancers. Modelling 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. Targeting essential genes in deleted regions of chromosome 3p could represent a potential preventative strategy for renal cancer.