Genomics of lethal prostate cancer at diagnosis and castration resistance

J Clin Invest. 2020 Apr 1;130(4):1743-1751. doi: 10.1172/JCI132031.


The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.

Keywords: Cancer; Cell Biology; Molecular biology; Oncology; Prostate cancer.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Disease-Free Survival
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Genomics*
  • Humans
  • Male
  • Neoplasm Proteins* / biosynthesis
  • Neoplasm Proteins* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Prostatic Neoplasms, Castration-Resistant* / mortality
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Survival Rate


  • Neoplasm Proteins