EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100412571EGA dataset EGAD00001004125EGAProstate 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 report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer.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 RABova G Steven GS, Kallio Heini M L HM, Annala Matti M, Kivinummi Kati K, Högnäs Gunilla G, Häyrynen Sergei S, Rantapero Tommi T, Kivinen Virpi V, Isaacs William B WB, Tolonen Teemu T, Nykter Matti M, Visakorpi Tapio TfalseEGAS00001000262-sc-20180521 - samplesData collected as part of the Normal prostatectomy project analysis. Whole genome sequencing (WGS, targeted at 30X for normal tissue and 50X for tumour tissue) was performed on morphologically normal tissue samples from 30 patients with prostate cancer. In addition, seven prostate tissue samples were sequenced from 7 non-cancer patients: two collected after a cystoprostatectomy and five from samples collected at autopsy. Matched blood controls were included for all patients. An extra five samples were sequenced from the stroma of cell cultured fibroblasts. In addition a few tumour samples obtained at prostatectomy and their blood matched controls are included in this dataset from the main study that are not included elsewhere.2021-09-07 08:19:57EGAD0000100412596062966216727148588EGAC00001000010EGAS00001000262