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Updated: Dec 27, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer
Himisha Beltran1,2, Alessandro Romanel3, Vincenza Conteduca1,4
1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Abstract:
Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.
Insights
Detecting neuroendocrine prostate cancer (CRPC-NE) transformation is possible using cell-free DNA (cfDNA) analysis. This liquid biopsy approach identifies genomic and epigenomic CRPC-NE features in circulation, offering a less invasive diagnostic alternative.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Advanced prostate cancer can transform into castration-resistant neuroendocrine prostate cancer (CRPC-NE), a challenging diagnosis.
- Current CRPC-NE diagnosis requires invasive tumor biopsies, often complicated by heterogeneity.
Purpose of the Study:
- To identify CRPC-NE features in cell-free DNA (cfDNA) for a less invasive diagnostic method.
- To compare cfDNA and biopsy tissue genomic and epigenomic alterations in CRPC-NE patients.
Main Methods:
- Whole-exome and whole-genome bisulfite sequencing of cfDNA and matched tumor biopsies.
- Analysis of allele-specific copy number and serial cfDNA sampling.
- Assessment of cfDNA methylation patterns and targeted genomic/epigenomic alterations.
Main Results:
- CRPC-NE features were detectable in cfDNA, showing higher concordance with biopsy data than in other castration-resistant types.
- cfDNA methylation correlated with tumor content and reflected CRPC-NE-specific epigenetic changes.
- A targeted panel of genomic and epigenomic alterations in ctDNA identified patients with CRPC-NE.
Conclusions:
- cfDNA analysis offers a promising, less invasive method for diagnosing CRPC-NE.
- Genomic and epigenomic profiling of cfDNA can track tumor evolution and identify specific CRPC-NE transformations.
