Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 682-692 |
| Number of pages | 11 |
| Journal | Nature genetics |
| Volume | 50 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2018 |
ASJC Scopus subject areas
- Genetics
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Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. / Wedge, David C.; Gundem, Gunes; Mitchell, Thomas; Woodcock, Dan J.; Martincorena, Inigo; Ghori, Mohammed; Zamora, Jorge; Butler, Adam; Whitaker, Hayley; Kote-Jarai, Zsofia; Alexandrov, Ludmil B.; Van Loo, Peter; Massie, Charlie E.; Dentro, Stefan; Warren, Anne Y.; Verrill, Clare; Berney, Dan M.; Dennis, Nening; Merson, Sue; Hawkins, Steve; Howat, William; Lu, Yong Jie; Lambert, Adam; Kay, Jonathan; Kremeyer, Barbara; Karaszi, Katalin; Luxton, Hayley; Camacho, Niedzica; Marsden, Luke; Edwards, Sandra; Matthews, Lucy; Bo, Valeria; Leongamornlert, Daniel; McLaren, Stuart; Ng, Anthony; Yu, Yongwei; Zhang, Hongwei; Dadaev, Tokhir; Thomas, Sarah; Easton, Douglas F.; Ahmed, Mahbubl; Bancroft, Elizabeth; Fisher, Cyril; Livni, Naomi; Nicol, David; Tavaré, Simon; Gill, Pelvender; Greenman, Christopher; Khoo, Vincent; Van As, Nicholas; Kumar, Pardeep; Ogden, Christopher; Cahill, Declan; Thompson, Alan; Mayer, Erik; Rowe, Edward; Dudderidge, Tim; Gnanapragasam, Vincent; Shah, Nimish C.; Raine, Keiran; Jones, David; Menzies, Andrew; Stebbings, Lucy; Teague, Jon; Hazell, Steven; Corbishley, Cathy; De Bono, Johann; Attard, Gerhardt; Isaacs, William; Visakorpi, Tapio; Fraser, Michael; Boutros, Paul C.; Bristow, Robert G.; Workman, Paul; Sander, Chris; Hamdy, Freddie C.; Futreal, Andrew; McDermott, Ultan; Al-Lazikani, Bissan; Lynch, Andrew G.; Bova, G. Steven; Foster, Christopher S.; Brewer, Daniel S.; Neal, David E.; Cooper, Colin S.; Eeles, Rosalind A.
In: Nature genetics, Vol. 50, No. 5, 01.05.2018, p. 682-692.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets
AU - Wedge, David C.
AU - Gundem, Gunes
AU - Mitchell, Thomas
AU - Woodcock, Dan J.
AU - Martincorena, Inigo
AU - Ghori, Mohammed
AU - Zamora, Jorge
AU - Butler, Adam
AU - Whitaker, Hayley
AU - Kote-Jarai, Zsofia
AU - Alexandrov, Ludmil B.
AU - Van Loo, Peter
AU - Massie, Charlie E.
AU - Dentro, Stefan
AU - Warren, Anne Y.
AU - Verrill, Clare
AU - Berney, Dan M.
AU - Dennis, Nening
AU - Merson, Sue
AU - Hawkins, Steve
AU - Howat, William
AU - Lu, Yong Jie
AU - Lambert, Adam
AU - Kay, Jonathan
AU - Kremeyer, Barbara
AU - Karaszi, Katalin
AU - Luxton, Hayley
AU - Camacho, Niedzica
AU - Marsden, Luke
AU - Edwards, Sandra
AU - Matthews, Lucy
AU - Bo, Valeria
AU - Leongamornlert, Daniel
AU - McLaren, Stuart
AU - Ng, Anthony
AU - Yu, Yongwei
AU - Zhang, Hongwei
AU - Dadaev, Tokhir
AU - Thomas, Sarah
AU - Easton, Douglas F.
AU - Ahmed, Mahbubl
AU - Bancroft, Elizabeth
AU - Fisher, Cyril
AU - Livni, Naomi
AU - Nicol, David
AU - Tavaré, Simon
AU - Gill, Pelvender
AU - Greenman, Christopher
AU - Khoo, Vincent
AU - Van As, Nicholas
AU - Kumar, Pardeep
AU - Ogden, Christopher
AU - Cahill, Declan
AU - Thompson, Alan
AU - Mayer, Erik
AU - Rowe, Edward
AU - Dudderidge, Tim
AU - Gnanapragasam, Vincent
AU - Shah, Nimish C.
AU - Raine, Keiran
AU - Jones, David
AU - Menzies, Andrew
AU - Stebbings, Lucy
AU - Teague, Jon
AU - Hazell, Steven
AU - Corbishley, Cathy
AU - De Bono, Johann
AU - Attard, Gerhardt
AU - Isaacs, William
AU - Visakorpi, Tapio
AU - Fraser, Michael
AU - Boutros, Paul C.
AU - Bristow, Robert G.
AU - Workman, Paul
AU - Sander, Chris
AU - Hamdy, Freddie C.
AU - Futreal, Andrew
AU - McDermott, Ultan
AU - Al-Lazikani, Bissan
AU - Lynch, Andrew G.
AU - Bova, G. Steven
AU - Foster, Christopher S.
AU - Brewer, Daniel S.
AU - Neal, David E.
AU - Cooper, Colin S.
AU - Eeles, Rosalind A.
N1 - Funding Information: The authors thank those men with prostate cancer and the subjects who have donated their time and their samples to the Cambridge, Oxford, The Institute of Cancer Research, John Hopkins and University of Tampere BioMediTech Biorepositories for this study. We also acknowledge support of the research staff in S4 who so carefully curated the samples and the follow-up data (J. Burge, M. Corcoran, A. George and S. Stearn). We thank M. Stratton for discussions when setting up the CR-UK Prostate Cancer ICGC Project. We acknowledge support from Cancer Research UK C5047/A14835/A22530/ A17528, C309/A11566, C368/A6743, A368/A7990, C14303/A17197 (Z.K.-J., S. Merson, N.C., S.E., D.L., T. Dadaev, M.A., E.B., J.B., G.A., P.W., B.A.-L., D.S.B., C.S.C., R.A.E.), the Dallaglio Foundation (CR-UK Prostate Cancer ICGC Project and Pan Prostate Cancer Group), PC-UK/Movember (Z.K.-J.), the NIHR support to The Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust (Z.K.-J., N.D., S. Merson, N.C., S.E., D.L., T. Dadaev, S. Thomas, M.A., E.B., C.F., N.L., D.N., V.K., N.A., P.K., C.O., D.C., A.T., E.M., E.R., T. Dudderidge, S. Hazell, J.B., G.A., P.W., B.A.-L., D.S.B., C.S.C., R.A.E.), Cancer Research UK funding to The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust CRUK Centre, the National Cancer Research Institute (National Institute of Health Research (NIHR) Collaborative Study: “Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)” (grant G0500966/75466) (D.E.N., V.G.), the Li Ka Shing Foundation (D.C.W., D.J.W.) and the Academy of Finland and Cancer Society of Finland (G.S.B.). We thank the National Institute for Health Research, Hutchison Whampoa Limited, University of Cambridge and the Human Research Tissue Bank (Addenbrooke’s Hospital), which is supported by the NIHR Cambridge Biomedical Research Centre; The Core Facilities at the Cancer Research UK Cambridge Institute, Orchid and Cancer Research UK, D. Holland from the Infrastructure Management Team, and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. D.M.B. is supported by Orchid. C.V.’s academic time was supported by the NIHR Oxford Biomedical Research Centre (Molecular Diagnostics Theme/Multimodal Pathology sub-theme). We also acknowledge support from the Bob Champion Cancer Trust, The Masonic Charitable Foundation successor to The Grand Charity, The King Family and the Stephen Hargrave Trust (C.S.C., D.S.B.). P.W. is a Cancer Research Life Fellow. We acknowledge core facilities provided by CRUK funding to the CRUK ICR Centre, the CRUK Cancer Therapeutics Unit and support for canSAR C35696/A23187 (P.W., G.A.).
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045439918&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045439918&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0086-z
DO - 10.1038/s41588-018-0086-z
M3 - Article
C2 - 29662167
AN - SCOPUS:85045439918
VL - 50
SP - 682
EP - 692
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 5
ER -