Neuroendocrine Prostate Cancer (Weill Cornell Medicine, Nature Medicine 2016)

Overview

The nepc_wcm_2016 cohort was generated by Beltran et al. at Weill Cornell Medicine and published in Nature Medicine 2016. It profiles 114 metastatic biopsies from 81 men with castration-resistant prostate cancer (CRPC) — 51 patients with adenocarcinoma histology (CRPC-Adeno, 70 samples) and 30 with neuroendocrine histology (CRPC-NE, 44 samples) — using whole-exome sequencing, RNA-seq, and genome-wide DNA methylation (eRRBS). Multi-region and serial biopsies were obtained from 17 patients. BAM files are deposited at dbGaP accession phs000909.v.p1 and hosted on cBioPortal for Cancer Genomics. PMID:26855148

Composition

  • 81 patients / 114 metastatic biopsies of castration-resistant prostate cancer (PRAD).
  • CRPC-Adeno: 51 patients, 70 samples.
  • CRPC-NE: 30 patients, 44 samples.
  • Matched normals from all patients; multi-region/serial biopsies from 17 patients.
  • All samples are metastatic biopsies (not primary tumors). PMID:26855148

Assays / panels (linked)

  • whole-exome-seq: SureSelect v2/v4 or HaloPlex Exome (Agilent), Illumina HiSeq, mean target coverage ~100×.
  • rna-seq: TruSeq, HiSeq 2500, 2×75 bp paired-end, on 49 specimens.
  • rrbs: Enhanced RRBS (eRRBS) for genome-wide single-cytosine methylation.
  • Custom NanoString assay for samples with limited material.
  • immunohistochemistry: AR, synaptophysin, chromogranin A, CD56, EZH2, MMR proteins.
  • fish: CYLD deletion verification.
  • Computational: MuTect, Oncotator, MutSig, CLONET for tumor purity/ploidy and allele-specific copy-number clonality. PMID:26855148

Papers using this cohort

  • PMID:26855148 — Beltran et al. 2016, Nature Medicine: Primary study defining the genomic, transcriptomic, and epigenomic landscape of CRPC-NE vs CRPC-Adeno; developed a 70-gene NEPC classifier with precision/recall >0.99.

Notable findings derived from this cohort

  • Concurrent RB1 loss + TP53 alteration is the genetic hallmark of CRPC-NE: RB1 deletion 70% vs 32% (P=0.003), TP53 mutation/deletion 66.7% vs 31.4% (P=0.0043), concurrent 53.3% vs 13.7% (P<0.0004). PMID:26855148
  • CRPC-NE lacks AR genomic alterations that dominate CRPC-Adeno (focal AR amplification, point mutations, ARv7 enrichment) — P<0.0001. PMID:26855148
  • CYLD focal deletion enriched in CRPC-NE (51% of samples, FDR<10%, FISH-verified), with concordant mRNA loss and modest AR-signaling attenuation. PMID:26855148
  • Strong epigenetic segregation of CRPC-NE from CRPC-Adeno despite overlapping somatic copy-number landscape; methylation-based clustering re-classified 3 histologic adenocarcinomas with clinical AR-independence as CRPC-NE. PMID:26855148
  • EZH2 mRNA 2× higher in CRPC-NE (P<10⁻⁶); EZH2 inhibitor GSK343 preferentially reduced viability of NCI-H660 (NE) vs non-NE cell lines. PMID:26855148
  • SPDEF promoter hypermethylation and mRNA silencing in CRPC-NE (P<10⁻⁹); also induced by long-term enzalutamide treatment of LNCaP adenocarcinoma cells — supporting divergent clonal evolution model. PMID:26855148
  • 70-gene integrated NEPC classifier (including AURKA P<10⁻⁵ and MYCN P<10⁻⁴) achieved precision/recall >0.99 in the discovery cohort; 0% of treatment-naïve adenocarcinomas scored NEPC-high vs up to 8% of metastatic cases across prad_tcga, prad_mich, and prad_su2c_2015. PMID:26855148

Sources

  • cBioPortal study: nepc_wcm_2016 — https://www.cbioportal.org/study/summary?id=nepc_wcm_2016
  • dbGaP accession: phs000909.v.p1
  • PMID:26855148 — Beltran et al. 2016, Nature Medicine.

This page was processed by crosslinker on 2026-05-14.