Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.
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Date
2018-05-01Author
Wedge, DC
Gundem, G
Mitchell, T
Woodcock, DJ
Martincorena, I
Ghori, M
Zamora, J
Butler, A
Whitaker, H
Kote-Jarai, Z
Alexandrov, LB
Van Loo, P
Massie, CE
Dentro, S
Warren, AY
Verrill, C
Berney, DM
Dennis, N
Merson, S
Hawkins, S
Howat, W
Lu, Y-J
Lambert, A
Kay, J
Kremeyer, B
Karaszi, K
Luxton, H
Camacho, N
Marsden, L
Edwards, S
Matthews, L
Bo, V
Leongamornlert, D
McLaren, S
Ng, A
Yu, Y
Zhang, H
Dadaev, T
Thomas, S
Easton, DF
Ahmed, M
Bancroft, E
Fisher, C
Livni, N
Nicol, D
Tavaré, S
Gill, P
Greenman, C
Khoo, V
Van As, N
Kumar, P
Ogden, C
Cahill, D
Thompson, A
Mayer, E
Rowe, E
Dudderidge, T
Gnanapragasam, V
Shah, NC
Raine, K
Jones, D
Menzies, A
Stebbings, L
Teague, J
Hazell, S
Corbishley, C
CAMCAP Study Group,
de Bono, J
Attard, G
Isaacs, W
Visakorpi, T
Fraser, M
Boutros, PC
Bristow, RG
Workman, P
Sander, C
TCGA Consortium,
Hamdy, FC
Futreal, A
McDermott, U
Al-Lazikani, B
Lynch, AG
Bova, GS
Foster, CS
Brewer, DS
Neal, DE
Cooper, CS
Eeles, RA
Type
Journal Article
Metadata
Show full item recordAbstract
Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.
Subject
CAMCAP Study Group
TCGA Consortium
Humans
Prostatic Neoplasms
Disease Progression
BRCA2 Protein
Mutation
Oncogenes
Adult
Aged
Aged, 80 and over
Middle Aged
Male
Hepatocyte Nuclear Factor 3-alpha
High-Throughput Nucleotide Sequencing
Research team
Computational Biology and Chemogenomics
Prostate Cancer Targeted Therapy Group
Oncogenetics
Stereotactic and Precision Body Radiotherapy
Language
eng
Date accepted
2018-02-22
License start date
2018-05
Citation
Nature genetics, 2018, 50 (5), pp. 682 - 692
Publisher
NATURE PUBLISHING GROUP