Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity

Mol Cancer Res. 2019 Jun;17(6):1235-1240. doi: 10.1158/1541-7786.MCR-18-1101. Epub 2019 Mar 27.


Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary. IMPLICATIONS: The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Biomarkers, Tumor / genetics
  • Biopsy / methods
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptors, Androgen / genetics
  • Transcription, Genetic / genetics*


  • Biomarkers, Tumor
  • Receptors, Androgen