{"doi":"10.1038/nature11125","title":"The mutational landscape of lethal castration-resistant prostate cancer","abstract":null,"journal":"Nature","year":2012,"id":615249,"datarank":1.1796053488608678,"base_score":7.86403565907245,"endowment":7.86403565907245,"self_citation_contribution":1.1796053488608678,"citation_network_contribution":0.0,"self_endowment_contribution":1.1796053488608678,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2601,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":25,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":133446,"name":"Yi-Mi Wu","orcid":null,"position":1,"is_corresponding":false},{"id":133447,"name":"Dan R. Robinson","orcid":null,"position":2,"is_corresponding":false},{"id":262041,"name":"Xuhong Cao","orcid":"0000-0002-2455-3086","position":3,"is_corresponding":false},{"id":51851,"name":"Saravana M. Dhanasekaran","orcid":null,"position":4,"is_corresponding":false},{"id":1585692,"name":"Amjad P. Khan","orcid":null,"position":5,"is_corresponding":false},{"id":234015,"name":"Michael J. Quist","orcid":null,"position":6,"is_corresponding":false},{"id":246397,"name":"Xiaojun Jing","orcid":"0000-0002-2497-7225","position":7,"is_corresponding":false},{"id":1182693,"name":"Robert J. Lonigro","orcid":null,"position":8,"is_corresponding":false},{"id":376564,"name":"J. Chad Brenner","orcid":"0000-0003-3238-1111","position":9,"is_corresponding":false},{"id":273893,"name":"Irfan A. Asangani","orcid":"0000-0001-5381-1702","position":10,"is_corresponding":false},{"id":686744,"name":"Bushra Ateeq","orcid":"0000-0003-4682-9773","position":11,"is_corresponding":false},{"id":1182682,"name":"Sang Y. Chun","orcid":null,"position":12,"is_corresponding":false},{"id":422614,"name":"Javed Siddiqui","orcid":"0009-0004-8251-4829","position":13,"is_corresponding":false},{"id":1585693,"name":"Lee Sam","orcid":null,"position":14,"is_corresponding":false},{"id":1585694,"name":"Matt Anstett","orcid":null,"position":15,"is_corresponding":false},{"id":64720,"name":"Rohit Mehra","orcid":null,"position":16,"is_corresponding":false},{"id":35299,"name":"John R. Prensner","orcid":"0000-0002-7024-636X","position":17,"is_corresponding":false},{"id":293078,"name":"Nallasivam Palanisamy","orcid":"0000-0002-0633-9772","position":18,"is_corresponding":false},{"id":1585695,"name":"Gregory A. Ryslik","orcid":null,"position":19,"is_corresponding":false},{"id":1794,"name":"Fabio Vandin","orcid":"0000-0003-2244-2320","position":20,"is_corresponding":false},{"id":106817,"name":"Benjamin J. Raphael","orcid":"0000-0003-1274-048X","position":21,"is_corresponding":false},{"id":112221,"name":"Lakshmi P. Kunju","orcid":null,"position":22,"is_corresponding":false},{"id":1135,"name":"Daniel R. Rhodes","orcid":"0000-0002-2021-4773","position":23,"is_corresponding":false},{"id":64727,"name":"Kenneth J. Pienta","orcid":"0000-0002-4138-2186","position":24,"is_corresponding":false},{"id":51796,"name":"Arul M. Chinnaiyan","orcid":"0000-0001-9282-3415","position":25,"is_corresponding":false},{"id":64721,"name":"Scott A. Tomlins","orcid":"0000-0001-8661-9821","position":26,"is_corresponding":false},{"id":230449,"name":"Catherine S. Grasso","orcid":"0000-0001-8632-4126","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The mutational landscape of lethal castration-resistant prostate cancer","abstract":"Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":25,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"22722839","pmcid":"PMC3396711","openalex_id":null,"authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"R01CA13287","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA132874","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U01 CA111275","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P50 CA69568","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32 CA009676","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA046592","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32 CA140044","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P50 CA069568","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U01 CA113913","title":null},{"funder_name":"National Institutes of Health","grant_id":"5U01CA113913-10","title":"Harvard/Michigan/Cornell Prostate Cancer Biomarker Clinical Validation Center"},{"funder_name":"National Institutes of Health","grant_id":"3P50CA069568-05S5","title":"BUTYRATE ON APOPTOSIS INDUCED BY RADIATION, HORMONE WITHDRAWAL AND CHEMOTHERAPY"},{"funder_name":"National Institutes of Health","grant_id":"2U01CA111275-06","title":"A Systems Biology Approach to the Development of Cancer Biomarkers"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA132874-03","title":"Molecuar Sub-typing of Prostate Cancer Based on Recurrent Gene Fusions"},{"funder_name":"Howard Hughes Medical Institute","grant_id":"","title":null}],"total_grants":14,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"closed","license":"Springer TDM","oa_locations":[{"url":"http://www.nature.com/articles/nature11125.pdf","host_type":"publisher"},{"url":"http://www.nature.com/articles/nature11125","host_type":"publisher"},{"url":"https://europepmc.org/articles/PMC3396711","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC3396711?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1038/nature11125","host_type":""},{"url":"https://europepmc.org/articles/pmc3396711?pdf=render","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/22722839","host_type":""},{"url":"http://dx.doi.org/10.1038/nature11125","host_type":""},{"url":"https://dx.doi.org/10.1038/nature11125","host_type":""},{"url":"https://hdl.handle.net/11577/3194454","host_type":""}],"fields_of_study":["0301 basic medicine","03 medical and health sciences"],"mesh_terms":["Cells, Cultured","Humans","Prostatic Neoplasms","Receptors, Androgen","Orchiectomy","Sequence Alignment","Signal Transduction","Cell Proliferation","Mutation","Molecular Sequence Data","Male","Hepatocyte Nuclear Factor 3-alpha"],"keywords":["Hepatocyte Nuclear Factor 3-alpha","Male","Cell Proliferation; Cells, Cultured; Hepatocyte Nuclear Factor 3-alpha; Humans; Male; Molecular Sequence Data; Mutation; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Sequence Alignment; Signal Transduction; Multidisciplinary","Molecular Sequence Data","Prostatic Neoplasms","Article","Receptors, Androgen","Mutation","Humans","Orchiectomy","Sequence Alignment","Cells, Cultured","Cell Proliferation","Signal Transduction"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.12269879.v1","title":"Additional file 1 of Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.12269879","title":"Additional file 1 of Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13467457.v1","title":"Additional file 1 of Convergent network effects along the axis of gene expression during prostate cancer progression","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13467457","title":"Additional file 1 of Convergent network effects along the axis of gene expression during prostate cancer progression","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13467473.v1","title":"Additional file 8 of Convergent network effects along the axis of gene expression during prostate cancer progression","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13467473","title":"Additional file 8 of Convergent network effects along the axis of gene expression during prostate cancer progression","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.19728305.v1","title":"Additional file 1 of Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.19728305","title":"Additional file 1 of Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.23001902.v1","title":"Additional file 1 of Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.23001902","title":"Additional file 1 of Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.23001905.v1","title":"Additional file 2 of Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.23001905","title":"Additional file 2 of Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24165235.v1","title":"Additional file 1 of The heterogeneity and clonal evolution analysis of the advanced prostate cancer with castration resistance","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24165235","title":"Additional file 1 of The heterogeneity and clonal evolution analysis of the advanced prostate cancer with castration resistance","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24303277.v1","title":"Additional file 1 of Cancer origin tracing and timing in two high-risk prostate cancers using multisample whole genome analysis: prospects for personalized medicine","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24303277","title":"Additional file 1 of Cancer origin tracing and timing in two high-risk prostate cancers using multisample whole genome analysis: prospects for personalized medicine","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25824676.v1","title":"Additional file 1 of PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25824676.v2","title":"Additional file 1 of PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25824676","title":"Additional file 1 of PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25824877.v1","title":"Additional file 2 of PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25824877","title":"Additional file 2 of PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26580461.v1","title":"Additional file 1 of Photothermal therapy of papillary thyroid cancer tumor xenografts with targeted thyroid stimulating hormone receptor antibody functionalized multiwalled carbon nanotubes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26580461","title":"Additional file 1 of Photothermal therapy of papillary thyroid cancer tumor xenografts with targeted thyroid stimulating hormone receptor antibody functionalized multiwalled carbon nanotubes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26580464.v1","title":"Additional file 2 of Photothermal therapy of papillary thyroid cancer tumor xenografts with targeted thyroid stimulating hormone receptor antibody functionalized multiwalled carbon nanotubes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26580464","title":"Additional file 2 of Photothermal therapy of papillary thyroid cancer tumor xenografts with targeted thyroid stimulating hormone receptor antibody functionalized multiwalled carbon nanotubes","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T19:29:21.856093Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}