{"entity":{"id":"paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020","kind":"paper","name":"Genomics of lethal prostate cancer at diagnosis and castration resistance","aka":[],"tldr":"Sequencing the original diagnostic biopsies of men who later died of prostate cancer showed the dangerous changes were already there at the start, years before the disease became resistant.","summary":"Genomic aberrations were studied in primary prostate cancer diagnostic biopsies from men who went on to develop metastatic castration-resistant prostate cancer, with matching same-patient diagnostic and castration-resistant biopsies for a subset. Four hundred and seventy treatment-naive diagnostic biopsies were profiled by targeted and low-pass whole-genome sequencing, with 61 matched castration-resistant biopsies. TP53 was altered in 27% and PTEN in 12%, with DNA damage repair gene defects in BRCA2 at 7%, CDK12 at 5% and ATM at 4%. TP53, BRCA2 and CDK12 mutations were markedly more common than in the TCGA primary cohort. Men whose primary tumour carried RB1 loss had a worse prognosis. Among the 61 men with matched biopsies, differences were identified in AR, TP53, RB1 and PI3K or AKT mutational status between the two time points.","asOf":"2026-09-25","links":[{"label":"Mateo et al., J Clin Invest 2020: genomics of 470 diagnostic biopsies from men who went on to develop metastatic castration-resistant disease, with 61 matched later biopsies","url":"https://doi.org/10.1172/JCI132031"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31874108/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["cgp","wes-wgs"],"targets":["tp53","pten","brca","cdk12","atm","rb1","androgen-receptor"],"drugs":[],"companies":[],"institutions":[],"pathways":["homologous-recombination-repair","p53-cell-cycle","ar-signaling","pi3k-akt-mtor","clonal-evolution"],"terms":["biopsy","castration-resistance","driver-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jci"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Investigation","year":2020,"doi":"10.1172/JCI132031","pmid":"31874108","authors":"Mateo J, Seed G, Bertan C, et al.","paperType":"observational","findings":["TP53 altered in 27% and PTEN in 12% of diagnostic biopsies from men who later developed castration-resistant disease.","BRCA2 7%, CDK12 5% and ATM 4% at diagnosis, similar to the prevalence in castration-resistant disease.","RB1 loss in the primary tumour associated with worse prognosis.","AR, TP53, RB1 and PI3K/AKT status differed between paired diagnostic and castration-resistant samples."],"whatItMeans":"It splits the alterations into two groups with different practical meanings. The repair defects are present at diagnosis at close to their castration-resistant prevalence, so testing early is worthwhile; AR, TP53 and RB1 changes accumulate later, so a diagnostic sample does not answer questions about the disease in front of you at relapse.","caveats":["Selected by outcome: these are the primaries of men who went on to die of the disease, so the prevalences are not those of prostate cancer generally.","Targeted and low-pass sequencing on archival diagnostic biopsies, which are small and often decades old.","Sixty-one matched pairs is a small number on which to describe evolution."],"changedPractice":false,"participants":470},"route":"/key-papers/paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020/","neighbours":{"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/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"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":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"cdk12","kind":"target","name":"CDK12","route":"/targets/cdk12/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"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":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"}],"term":[{"id":"biopsy","kind":"term","name":"Biopsy","route":"/terms/biopsy/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"}],"journal":[{"id":"jci","kind":"journal","name":"Journal of Clinical Investigation","route":"/journals/jci/"}]}}