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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.

SUBMITTER: Wedge DC

PROVIDER: S-EPMC6372064 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

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

Nature genetics 20180416 5

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 mutat ...[more]

PMID: 29662167

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Project description:PTOV1 is an adaptor protein with functions in diverse processes, including gene transcription and protein translation, whose overexpression is associated with a higher proliferation index and tumor grade in prostate cancer (PC) and other neoplasms. Here we report its interaction with the Notch pathway and its involvement in PC progression.Stable PTOV1 knockdown or overexpression were performed by lentiviral transduction. Protein interactions were analyzed by co-immunoprecipitation, pull-down and/or immunofluorescence. Endogenous gene expression was analyzed by real time RT-PCR and/or Western blotting. Exogenous promoter activities were studied by luciferase assays. Gene promoter interactions were analyzed by chromatin immunoprecipitation assays (ChIP). In vivo studies were performed in the Drosophila melanogaster wing, the SCID-Beige mouse model, and human prostate cancer tissues and metastasis. The Excel package was used for statistical analysis.Knockdown of PTOV1 in prostate epithelial cells and HaCaT skin keratinocytes caused the upregulation, and overexpression of PTOV1 the downregulation, of the Notch target genes HEY1 and HES1, suggesting that PTOV1 counteracts Notch signaling. Under conditions of inactive Notch signaling, endogenous PTOV1 associated with the HEY1 and HES1 promoters, together with components of the Notch repressor complex. Conversely, expression of active Notch1 provoked the dismissal of PTOV1 from these promoters. The antagonist role of PTOV1 on Notch activity was corroborated in the Drosophila melanogaster wing, where human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed the effects of constitutively active Notch. PTOV1 was required for optimal in vitro invasiveness and anchorage-independent growth of PC-3 cells, activities counteracted by Notch, and for their efficient growth and metastatic spread in vivo. In prostate tumors, the overexpression of PTOV1 was associated with decreased expression of HEY1 and HES1, and this correlation was significant in metastatic lesions.High levels of the adaptor protein PTOV1 counteract the transcriptional activity of Notch. Our evidences link the pro-oncogenic and pro-metastatic effects of PTOV1 in prostate cancer to its inhibitory activity on Notch signaling and are supportive of a tumor suppressor role of Notch in prostate cancer progression.

Dataset Information

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

Publications

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

Similar Datasets

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