# Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer

Source: https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/  
OnCo record `paper-beltran-nepc-divergent-evolution-nat-med-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing showed that neuroendocrine prostate cancer arises from the same cells as ordinary prostate adenocarcinoma but diverges through loss of RB1 and TP53 and changes in DNA methylation rather than new mutations, explaining how the cancer escapes hormone therapy by changing identity.

## Summary

Whole-exome and methylation analysis of 114 metastatic biopsies from patients with castration-resistant prostate cancer, comparing adenocarcinoma with neuroendocrine prostate cancer.

Neuroendocrine tumours shared clonal origin with adenocarcinoma, showed frequent RB1 loss and TP53 mutation, low androgen receptor signalling, distinct epigenetic profiles and overexpression of EZH2, with a lineage-switch rather than a distinct mutational driver.

## Fields

- Kind: Key paper
- Last checked: 2026-09-17
- Journal: Nature Medicine
- Year: 2016
- DOI: 10.1038/nm.4045
- Authors: Beltran H, Prandi D, Mosquera JM, et al.
- Findings: RB1 loss and TP53 alteration enriched in neuroendocrine prostate cancer.; Epigenetic divergence with shared clonal ancestry from adenocarcinoma.
- What it means: Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation.
- Caveats: Biopsy cohort from selected patients; therapeutic implications are still being tested.

## Sources

- Nat Med 2016: https://doi.org/10.1038/nm.4045
- PubMed: https://pubmed.ncbi.nlm.nih.gov/26855148/

## Connected records

- cancers: [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)

---
JSON: https://onco.cc/api/v1/entities/paper-beltran-nepc-divergent-evolution-nat-med-2016.json