Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.
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Date
2018-04-19Author
Turajlic, S
Xu, H
Litchfield, K
Rowan, A
Horswell, S
Chambers, T
O'Brien, T
Lopez, JI
Watkins, TBK
Nicol, D
Stares, M
Challacombe, B
Hazell, S
Chandra, A
Mitchell, TJ
Au, L
Eichler-Jonsson, C
Jabbar, F
Soultati, A
Chowdhury, S
Rudman, S
Lynch, J
Fernando, A
Stamp, G
Nye, E
Stewart, A
Xing, W
Smith, JC
Escudero, M
Huffman, A
Matthews, N
Elgar, G
Phillimore, B
Costa, M
Begum, S
Ward, S
Salm, M
Boeing, S
Fisher, R
Spain, L
Navas, C
Grönroos, E
Hobor, S
Sharma, S
Aurangzeb, I
Lall, S
Polson, A
Varia, M
Horsfield, C
Fotiadis, N
Pickering, L
Schwarz, RF
Silva, B
Herrero, J
Luscombe, NM
Jamal-Hanjani, M
Rosenthal, R
Birkbak, NJ
Wilson, GA
Pipek, O
Ribli, D
Krzystanek, M
Csabai, I
Szallasi, Z
Gore, M
McGranahan, N
Van Loo, P
Campbell, P
Larkin, J
Swanton, C
TRACERx Renal Consortium,
Type
Journal Article
Metadata
Show full item recordAbstract
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
Collections
Subject
TRACERx Renal Consortium
Chromosomes
Humans
Carcinoma, Renal Cell
Kidney Neoplasms
Neoplasm Metastasis
Disease Progression
Prognosis
Models, Statistical
Longitudinal Studies
Prospective Studies
Sequence Analysis, DNA
Evolution, Molecular
Phylogeny
Phenotype
Genetic Heterogeneity
Mutation
Alleles
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Genetic Variation
Clonal Evolution
Biomarkers, Tumor
Research team
Melanoma and Kidney Cancer
Experimental Pathology
Molecular & Population Genetics
Language
eng
Date accepted
2018-03-19
License start date
2018-04-12
Citation
Cell, 2018, 173 (3), pp. 595 - 610.e11
Publisher
CELL PRESS