# 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

- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- key papers: [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/)
- ideas: [Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it](https://onco.cc/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/)
- terms: [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Neuroendocrine differentiation in prostate cancer](https://onco.cc/terms/neuroendocrine-differentiation/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)
- biomarkers: [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)

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