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

TLDR

Clear cell renal cell carcinoma is almost universally driven by loss of chromosome 3p, which deletes multiple tumor‑suppressor genes. We performed whole‑genome sequencing on 95 biopsies from 33 patients to map genomic alterations. The study identified recurrent TERT 5′‑UTR mutations, frequent 3p loss coupled with 5q gain via chromothripsis that arise in childhood or adolescence, and showed that only a few hundred 3p‑deficient cells can initiate sporadic tumors, revealing defined evolutionary trajectories that suggest a window for early intervention.

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. Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.