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

David C. Wedge; Gunes Gundem; Thomas Mitchell; Dan J. Woodstock; Inigo Martincorena; Mohammed Ghori; Jorge Zamora; Adam Butler; Hayley Whitaker; Zsofia Kote-Jarai; Lumil B. Alexandrov; Peter Van Loo; Charlie E. Massie; Stefan Dentro; Anne Y. Warren; Clare Verrill; Dan M. Berney; Nening Dennis; Sue Merson; Steve Hawkins; William Howat; Yong-Jie Lu; Adam Lambert; Jonathan Kay; Barbara Kremeyer; Katalin Karaszi; Niedzica Camacho; Hayley Luxton; 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; CamCaP Study Group; Johann de Bono; Gerhardt Attard; William Isaacs; Tapio Visakorpi; Michael Fraser; Paul C. Boutros; Robert G. Bristow; Paul Workman; Chris Sander; The TCGA Consortium; 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

doi:10.1038/s41588-018-0086-z

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

David C. Wedge, Gunes Gundem, Thomas Mitchell, Dan J. Woodstock, Inigo Martincorena, Mohammed Ghori, Jorge Zamora, Adam Butler, Hayley Whitaker, Zsofia Kote-Jarai, Lumil B. Alexandrov, Peter Van Loo, Charlie E. Massie, Stefan Dentro, Anne Y. Warren, Clare Verrill, Dan M. Berney, Nening Dennis, Sue Merson, Steve HawkinsWilliam Howat, Yong-Jie Lu, Adam Lambert, Jonathan Kay, Barbara Kremeyer, Katalin Karaszi, Niedzica Camacho, Hayley Luxton, 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, CamCaP Study Group, Johann de Bono, Gerhardt Attard, William Isaacs, Tapio Visakorpi, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Paul Workman, Chris Sander, The TCGA Consortium, 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

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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
Pages (from-to)	682-692
Number of pages	16
Journal	Nature Genetics
Volume	50
Issue number	5
Early online date	16 Apr 2018
DOIs	https://doi.org/10.1038/s41588-018-0086-z
Publication status	Published - May 2018

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© 2018, Nature American Inc., part of Springer Nature. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1038/s41588-018-0086-z
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Wedge, D. C., Gundem, G., Mitchell, T., Woodstock, D. J., Martincorena, I., Ghori, M., Zamora, J., Butler, A., Whitaker, H., Kote-Jarai, Z., Alexandrov, L. B., Van Loo, P., Massie, C. E., Dentro, S., Warren, A. Y., Verrill, C., Berney, D. M., Dennis, N., Merson, S., ... 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

@article{3719fd1106b6491fb09dfc9101b52437,

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

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.",

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

year = "2018",

month = may,

doi = "10.1038/s41588-018-0086-z",

language = "English",

volume = "50",

pages = "682--692",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

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Wedge, DC, Gundem, G, Mitchell, T, Woodstock, 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, Camacho, N, Luxton, H, 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, The 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 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

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AU - Wedge, David C.

AU - Gundem, Gunes

AU - Mitchell, Thomas

AU - Woodstock, Dan J.

AU - Martincorena, Inigo

AU - Ghori, Mohammed

AU - Zamora, Jorge

AU - Butler, Adam

AU - Whitaker, Hayley

AU - Kote-Jarai, Zsofia

AU - Alexandrov, Lumil B.

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AU - Warren, Anne Y.

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AU - Lu, Yong-Jie

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AU - Edwards, Sandra

AU - Matthews, Lucy

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AU - Leongamornlert, Daniel

AU - McLaren, Stuart

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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 - CamCaP Study Group

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 - The TCGA Consortium

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.

PY - 2018/5

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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.

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U2 - 10.1038/s41588-018-0086-z

DO - 10.1038/s41588-018-0086-z

M3 - Article

SN - 1061-4036

VL - 50

SP - 682

EP - 692

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

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