Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

David C. Wedge, Gunes Gundem, Thomas Mitchell, Dan J. Woodcock, Inigo Martincorena, Mohammed Ghori, Jorge Zamora, Adam Butler, Hayley Whitaker, Zsofia Kote-Jarai, Ludmil B. Alexandrov, Peter Van Loo, Charlie E. Massie, Stefan Dentro, Anne Y. Warren, Clare Verrill, Dan M. Berney, Nening Dennis, Sue Merson, Steve Hawkins & 66 others William Howat, Yong Jie Lu, Adam Lambert, Jonathan Kay, Barbara Kremeyer, Katalin Karaszi, Hayley Luxton, Niedzica Camacho, Luke Marsden, Sandra Edwards, Lucy Matthews, Valeria Bo, Daniel Leongamornlert, Stuart McLaren, Anthony Ng, Yongwei Yu, Hongwei Zhang, Tokhir Dadaev, Sarah Thomas, Douglas F. Easton, Mahbubl Ahmed, Elizabeth Bancroft, Cyril Fisher, Naomi Livni, David Nicol, Simon Tavaré, Pelvender Gill, Christopher Greenman, Vincent Khoo, Nicholas Van As, Pardeep Kumar, Christopher Ogden, Declan Cahill, Alan Thompson, Erik Mayer, Edward Rowe, Tim Dudderidge, Vincent Gnanapragasam, Nimish C. Shah, Keiran Raine, David Jones, Andrew Menzies, Lucy Stebbings, Jon Teague, Steven Hazell, Cathy Corbishley, Johann De Bono, Gerhardt Attard, William B Isaacs, Tapio Visakorpi, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Paul Workman, Chris Sander, Freddie C. Hamdy, Andrew Futreal, Ultan McDermott, Bissan Al-Lazikani, Andrew G. Lynch, G. Steven Bova, Christopher S. Foster, Daniel S. Brewer, David E. Neal, Colin S. Cooper, Rosalind A. Eeles

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)682-692
Number of pages11
JournalNature Genetics
Volume50
Issue number5
DOIs
StatePublished - May 1 2018

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Neoplasm Genes
Prostatic Neoplasms
Mutation
Pharmaceutical Preparations
Neoplasms
Investigational Drugs
Dissection
Clinical Trials
Genome
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Wedge, D. C., Gundem, G., Mitchell, T., Woodcock, D. J., Martincorena, I., Ghori, M., ... Eeles, R. A. (2018). Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nature Genetics, 50(5), 682-692. https://doi.org/10.1038/s41588-018-0086-z

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 B; 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 journalArticle

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, YJ, 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, De Bono, J, Attard, G, Isaacs, WB, Visakorpi, T, Fraser, M, Boutros, PC, Bristow, RG, Workman, P, Sander, C, Hamdy, FC, Futreal, A, McDermott, U, Al-Lazikani, B, Lynch, AG, Bova, GS, Foster, CS, Brewer, DS, Neal, DE, Cooper, CS & Eeles, RA 2018, 'Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets', Nature Genetics, vol. 50, no. 5, pp. 682-692. https://doi.org/10.1038/s41588-018-0086-z
Wedge DC, Gundem G, Mitchell T, Woodcock DJ, Martincorena I, Ghori M et al. Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nature Genetics. 2018 May 1;50(5):682-692. https://doi.org/10.1038/s41588-018-0086-z
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 B ; 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. / Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. In: Nature Genetics. 2018 ; Vol. 50, No. 5. pp. 682-692.
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