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; 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 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

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. 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 HawkinsWilliam 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 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

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	https://doi.org/10.1038/s41588-018-0086-z
State	Published - May 1 2018

ASJC Scopus subject areas

Genetics

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10.1038/s41588-018-0086-z

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Wedge, D. C., Gundem, G., Mitchell, T., Woodcock, 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

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, W, 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

@article{1d3d2d61f65e4bd6b0f8dce2ab1ec1ae,

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 Woodcock, {Dan J.} and Inigo Martincorena and Mohammed Ghori and Jorge Zamora and Adam Butler and Hayley Whitaker and Zsofia Kote-Jarai and Alexandrov, {Ludmil 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 Lu, {Yong Jie} and Adam Lambert and Jonathan Kay and Barbara Kremeyer and Katalin Karaszi and Hayley Luxton and Niedzica Camacho 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 {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 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.}",

note = "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{\textquoteright}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.{\textquoteright}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.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = may,

day = "1",

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

language = "English (US)",

volume = "50",

pages = "682--692",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

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.). Publisher Copyright: © 2018 The Author(s).

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.

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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 -

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

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