Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.
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ICR Authors
Authors
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,
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,
Document Type
Journal Article
Date
2018-04-19
Date Accepted
2018-02-07
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.
Citation
Cell, 2018, 173 (3), pp. 611 - 623.e17
Source Title
Cell
Publisher
CELL PRESS
ISSN
0092-8674
eISSN
1097-4172
1097-4172
1097-4172
Collections
Research Team
Experimental Pathology
Melanoma & Kidney Cancer
RMH Honorary Faculty
Melanoma & Kidney Cancer
RMH Honorary Faculty