Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer
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.
Overview
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.
- RB1 loss and TP53 alteration enriched in neuroendocrine prostate cancer.
- Epigenetic divergence with shared clonal ancestry from adenocarcinoma.
Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation.
- Biopsy cohort from selected patients; therapeutic implications are still being tested.