Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer.
J Clin Invest
; 130(4): 1653-1668, 2020 04 01.
Article
en En
| MEDLINE
| ID: mdl-32091413
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Adenocarcinoma
/
Regulación Neoplásica de la Expresión Génica
/
Carcinoma Neuroendocrino
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Metilación de ADN
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Epigénesis Genética
/
Neoplasias de la Próstata Resistentes a la Castración
/
ADN Tumoral Circulante
/
Proteínas de Neoplasias
Tipo de estudio:
Observational_studies
/
Risk_factors_studies
Límite:
Humans
/
Male
Idioma:
En
Revista:
J Clin Invest
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos