{"entity":{"id":"paper-grasso-mutational-landscape-lethal-crpc-nature-2012","kind":"paper","name":"The mutational landscape of lethal castration-resistant prostate cancer","aka":["Grasso 2012","lethal CRPC exome rapid autopsy"],"tldr":"Fifty men who died of prostate cancer had their tumours sequenced within hours of death. Even after years of treatment the cancers carried few mutations, and the recurring ones were in genes that control how DNA is packaged and read rather than in classic cancer genes.","summary":"Catherine Grasso, Arul Chinnaiyan and colleagues sequenced the exomes of 50 lethal, heavily pre-treated metastatic castration-resistant prostate cancers obtained at rapid autopsy, including three separate deposits from one patient, alongside 11 treatment-naive high-grade localised cancers.\n\nThe low mutation rate, 2.00 per megabase even after years of therapy, is the number to remember: prostate cancer is a structurally rearranged genome rather than a heavily mutated one, which is why tumour mutational burden rarely qualifies it for immunotherapy. The recurrent mutations that were found sit in chromatin and histone-modifying genes and in the androgen receptor's collaborators, and the paper showed physical interaction between the MLL complex and the receptor. CHD1 disruption defined a subtype of ETS fusion-negative disease, and FOXA1 mutations were found in 5 of 147 tumours.","asOf":"2026-09-25","links":[{"label":"Nature 2012","url":"https://doi.org/10.1038/nature11125"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22722839/"},{"label":"cBioPortal study prad_mich (University of Michigan, Nature 2012; 61 samples, 50 lethal castration-resistant cancers at rapid autopsy and 11 treatment-naive primaries)","url":"https://www.cbioportal.org/study/summary?id=prad_mich"}],"tags":["prostate-evidence"],"related":["paper-baca-punctuated-evolution-chromoplexy-cell-2013","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["diagnostics","epigenetics"],"technologies":["wes-wgs"],"targets":["foxa1","erg","tmprss2","androgen-receptor","kmt2d","kmt2c"],"drugs":[],"companies":[],"institutions":["michigan-rogel"],"pathways":["ar-signaling","epigenetic-reprogramming","clonal-evolution","prostate-cancer-signalling"],"terms":["tmb","ngs","chromoplexy","driver-mutation","gene-fusion","castration-resistance","somatic-mutations-wxs-wgs"],"trials":[],"people":["arul-chinnaiyan"],"bottlenecks":["b-undruggable-targets","b-immunotherapy-response","b-tumor-heterogeneity"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature11125","pmid":"22722839","authors":"Grasso CS, Wu YM, Robinson DR, et al.","paperType":"basic","findings":["Low overall mutation rates even in heavily treated castration-resistant disease, at 2.00 per megabase, and confirmation of the monoclonal origin of lethal castration-resistant prostate cancer.","Disruptions of CHD1 define a subtype of ETS gene family fusion-negative prostate cancer.","Recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 in 8.6 percent of prostate cancers, with the MLL complex shown to interact with the androgen receptor as required for androgen receptor-mediated signalling.","Novel recurrent mutations in FOXA1 in 5 of 147 prostate cancers (3.4 percent), in both untreated localised disease and castration-resistant disease; mutated FOXA1 represses androgen signalling and increases tumour growth.","ETS2, deleted in approximately one third of castration-resistant cancers, commonly through TMPRSS2-ERG fusion, is also deregulated through mutation."],"whatItMeans":"The explanation for why prostate cancer has so few targeted drugs outside the hormone axis and the DNA-repair genes: it is a quiet genome with structural rather than point-mutational damage, and the recurrent changes sit in the machinery that reads DNA rather than in kinases.","caveats":["50 rapid-autopsy cases is a small and extreme sample, selected for death from the disease and for heavy prior treatment.","Exome sequencing misses the structural rearrangements that Baca and Gundem later showed dominate this cancer.","Mutation frequencies from 61 tumours are not population estimates; TCGA and the SU2C cohort give better ones."],"changedPractice":false,"participants":61},"route":"/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/","neighbours":{"paper":[{"id":"paper-taylor-integrative-genomic-profiling-cancer-cell-2010","kind":"paper","name":"Integrative genomic profiling of human prostate cancer","route":"/key-papers/paper-taylor-integrative-genomic-profiling-cancer-cell-2010/"},{"id":"paper-baca-punctuated-evolution-chromoplexy-cell-2013","kind":"paper","name":"Punctuated evolution of prostate cancer genomes","route":"/key-papers/paper-baca-punctuated-evolution-chromoplexy-cell-2013/"},{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","kind":"paper","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"epigenetics","kind":"section","name":"Epigenetic & Transcriptional Therapy","route":"/fronts/epigenetics/"}],"technology":[{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"erg","kind":"target","name":"ERG","route":"/targets/erg/"},{"id":"foxa1","kind":"target","name":"FOXA1","route":"/targets/foxa1/"},{"id":"kmt2c","kind":"target","name":"KMT2C","route":"/targets/kmt2c/"},{"id":"kmt2d","kind":"target","name":"KMT2D","route":"/targets/kmt2d/"},{"id":"tmprss2","kind":"target","name":"TMPRSS2","route":"/targets/tmprss2/"}],"institution":[{"id":"michigan-rogel","kind":"institution","name":"University of Michigan Rogel Cancer Center","route":"/institutions/michigan-rogel/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"prostate-cancer-signalling","kind":"pathway","name":"Prostate cancer (KEGG map)","route":"/pathways/prostate-cancer-signalling/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"chromoplexy","kind":"term","name":"Chromoplexy","route":"/terms/chromoplexy/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"somatic-mutations-wxs-wgs","kind":"term","name":"Somatic mutations from exome and genome sequencing (WXS, WGS)","route":"/terms/somatic-mutations-wxs-wgs/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"person":[{"id":"arul-chinnaiyan","kind":"person","name":"Arul M. Chinnaiyan","route":"/people/arul-chinnaiyan/"}],"bottleneck":[{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}