Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets
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Wedge, D., Gundem, G., Mitchell, T., Easton, D., & Gnanapragasam, V. (2018). Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nature Genetics https://doi.org/10.1038/s41588-018-0086-z
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.
We acknowledge support from Cancer Research UK C5047/A22530, C309/A11566, C368/A6743, A368/A7990, C14303/A17197 and the Dallaglio Foundation, The NIHR support to The Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust; 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); the Li Ka Shing foundation (DCW, DJW). The Academy of Finland and Cancer Society of Finland (GSB). We thank the National Institute for Health Research, Hutchison Whampoa Limited, University of Cambridge, 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, Dave Holland from the Infrastructure Management Team & Peter Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. DMB is supported by Orchid. We also acknowledge support from The Bob Champion Cancer Research Trust, The Masonic Charitable Foundation and The King Family. PW 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 and NIHR finding to the Biomedical Research Centre at Royal Marsden NHS Foundation Trust and Institute of Cancer Research.
Cancer Research UK (via Institute of Cancer Research (ICR)) (C5047/A22530)
Cancer Research UK (via Institute of Cancer Research (ICR)) (C5047/A14835)
External DOI: https://doi.org/10.1038/s41588-018-0086-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271640