# Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis

Source: https://onco.cc/key-papers/paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022/  
OnCo record `paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A blood test that reads chemical marks on DNA rather than its letters separated the aggressive neuroendocrine form of prostate cancer from the ordinary form almost perfectly.

## Summary

Neuroendocrine prostate cancer is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma and is difficult to detect in practice. Methylated DNA immunoprecipitation and high-throughput sequencing was performed on a training set of tumours, differentially methylated regions between neuroendocrine prostate cancer and castration-resistant adenocarcinoma were identified, and a model was built to predict the presence of neuroendocrine disease, termed a risk score. The same assay was then applied to cell-free DNA from two independent cohorts. The test cohort comprised 48 men, 9 with neuroendocrine disease and 39 with castration-resistant adenocarcinoma; risk scores were significantly higher in the neuroendocrine group and discriminated with an area under the receiver operating curve of 0.96, with the optimal cut-off giving 100% sensitivity and 90% specificity. The validation cohort included 53 men, 12 with neuroendocrine disease and 41 with adenocarcinoma; discrimination was perfect, area under the curve 1.0, and the predefined cut-off gave 100% sensitivity and 95% specificity.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Clinical Cancer Research
- Year: 2022
- DOI: 10.1158/1078-0432.CCR-21-3762
- Authors: Berchuck JE, Baca SC, McClure HM, et al.
- Findings: Risk score from cell-free DNA methylation discriminated neuroendocrine from castration-resistant adenocarcinoma with an area under the curve of 0.96 in the test cohort.; One hundred per cent sensitivity and 90% specificity at the optimal cut-off.; Perfect discrimination in an independent 53-man validation cohort, with 100% sensitivity and 95% specificity at the predefined cut-off.
- What it means: It is the right shape of answer for a transition that is epigenetic rather than genetic, and it could in principle spare the biopsy that is currently the only way to make this diagnosis.
- Caveats: Twenty-one men with neuroendocrine disease in total across both cohorts, so a perfect area under the curve should be read as promising rather than settled.; Methylated DNA immunoprecipitation sequencing is a research assay, not one that can be ordered.; The comparison is against a histological reference standard that is itself imperfect.

## Sources

- Berchuck et al., Clin Cancer Res 2022: tissue-informed cell-free DNA methylation to detect neuroendocrine prostate cancer (101 plasma samples in two cohorts): https://doi.org/10.1158/1078-0432.CCR-21-3762
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34907080/

## Connected records

- 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/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/)
- terms: [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/)
- journals: [Clinical Cancer Research](https://onco.cc/journals/clinical-cancer-research/)
- biomarkers: [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)

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