Prostate Neuroendocrine Carcinoma (PRNE)

Overview

Prostate neuroendocrine carcinoma (PRNE) — also called neuroendocrine prostate cancer (NEPC) — is a poorly differentiated carcinoma with neuroendocrine features that can arise de novo or as a treatment-emergent transformation from prostate adenocarcinoma (PRAD). On OncoTree it is a subtype of PROSTATE. It is characterized by loss of androgen receptor (AR) expression and resistance to androgen deprivation therapy.

Cohorts in the corpus

  • 44 PDX models from 38 prostate cancer patients at MD Anderson Cancer Center, spanning adenocarcinoma and neuroendocrine prostate cancer morphologies; profiled by WGS, T200.1 targeted sequencing, and RNA-seq. Dataset: prad_msk_mdanderson_2023. PMID:38488813
  • Included in secondary analysis of ATLAS lineage classifier; ATLAS differentiation score distinguished metastatic prostate adenocarcinoma from NEPC (AUC=0.834). PMID:27634761

Recurrent alterations

  • RB1 — deep deletions and mutations significantly more frequent in NEPC than adenocarcinoma (P=0.0002 for combined CNV + mutation). RB1 expression significantly lower in NEPC (P=9e-5). PMID:38488813
  • AR — expression significantly reduced in NEPC (P=4e-9); AR pathway loss is a hallmark of NEPC. PMID:38488813
  • TP53 — mutations frequent, higher in NEPC than adenocarcinoma. PMID:38488813
  • MYCN — elevated expression in NEPC without gene amplification; linked to DDR and neuroendocrine differentiation via MYCN-CDK5-RB1-E2F1 axis. PMID:38488813
  • AURKA — elevated expression in NEPC without gene amplification. PMID:38488813
  • NRAS — oncogenic Q61K mutation in NEPC PDX 144-4; rarely implicated in prostate cancer. PMID:38488813
  • KDM6A — deep deletion in NEPC pair 144. PMID:38488813
  • DNA damage response (DDR) pathway genes — transcriptomically upregulated in NEPC compared to adenocarcinoma PDXs; DDR gene expression clustering segregates models concordant with morphologic classification. PMID:38488813
  • Two PRNE metastases (post-castration) were included in a 57-tumor WGS cohort characterizing chromoplexy; the cohort was skewed to primary PRAD, leaving chromoplexy dynamics in neuroendocrine prostate cancer undercharacterized PMID:23622249

Subtypes

  • Treatment-emergent NEPC (tNEPC) vs. de novo NEPC: all PDX morphologies represented; NEPC PDXs showed the MYCN-CDK5-RB1-E2F1 neuroendocrine differentiation axis. PMID:38488813
  • ATLAS lineage de-differentiation score distinguished metastatic PRAD from NEPC with AUC=0.834, supporting RNA-based identification of NEPC transformation. PMID:27634761

Therapeutic landscape

  • DDR upregulation in NEPC, combined with evidence that PARP inhibition impairs MYCN-CDK5-RB1-E2F1-mediated neuroendocrine differentiation, supports investigation of PARP inhibitors in PRNE. PMID:38488813
  • Conserved driver alteration profiles in longitudinal PDX pairs suggest treatment resistance may be driven by non-genomic (epigenomic, microenvironmental) mechanisms. PMID:38488813

Sources

  • PMID:38488813 — Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft Series (Clinical Cancer Research, 2024)

  • PMID:27634761 — A platform-independent AI tumor lineage and site (ATLAS) classifier (Communications Biology, 2024)

  • PMID:23622249 — Baca et al. Punctuated evolution of prostate cancer genomes. Cell 2013.

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