Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.
Date
2018-04-19Author
Mitchell, TJ
Turajlic, S
Rowan, A
Nicol, D
Farmery, JHR
O'Brien, T
Martincorena, I
Tarpey, P
Angelopoulos, N
Yates, LR
Butler, AP
Raine, K
Stewart, GD
Challacombe, B
Fernando, A
Lopez, JI
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, DC
Horswell, S
Chambers, T
Litchfield, K
Xu, H
Stewart, A
Elaidi, R
Oudard, S
McGranahan, N
Csabai, I
Gore, M
Futreal, PA
Larkin, J
Lynch, AG
Szallasi, Z
Swanton, C
Campbell, PJ
TRACERx Renal Consortium,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
cancer evolution
chromothripsis
clear cell renal cell carcinoma
5' Untranslated Regions
Adult
Aged
Aged, 80 and over
Carcinoma, Renal Cell
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 5
Disease Progression
Female
Gene Dosage
Genome, Human
Humans
Kidney Neoplasms
Male
Middle Aged
Mutation
Prospective Studies
Telomerase
Von Hippel-Lindau Tumor Suppressor Protein
Research team
Experimental Pathology
Melanoma & Kidney Cancer
RMH Honorary Faculty
Language
eng
Date accepted
2018-02-07
License start date
2018-04-19
Citation
Cell, 2018, 173 (3), pp. 611 - 623.e17
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
http://creativecommons.org/licenses/by/4.0/
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