TY - JOUR
T1 - Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer
AU - Beltran, Himisha
AU - Romanel, Alessandro
AU - Conteduca, Vincenza
AU - Casiraghi, Nicola
AU - Sigouros, Michael
AU - Franceschini, Gian Marco
AU - Orlando, Francesco
AU - Fedrizzi, Tarcisio
AU - Ku, Sheng-Yu
AU - Dann, Emma
AU - Alonso, Alicia
AU - Mosquera, Juan Miguel
AU - Sboner, Andrea
AU - Xiang, Jenny
AU - Elemento, Olivier
AU - Nanus, David M
AU - Tagawa, Scott T
AU - Benelli, Matteo
AU - Demichelis, Francesca
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - Adenocarcinoma/blood
KW - Carcinoma, Neuroendocrine/blood
KW - Circulating Tumor DNA/blood
KW - DNA Methylation
KW - Epigenesis, Genetic
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Male
KW - Neoplasm Proteins/blood
KW - Prospective Studies
KW - Prostatic Neoplasms, Castration-Resistant/blood
U2 - 10.1172/JCI131041
DO - 10.1172/JCI131041
M3 - Article
C2 - 32091413
VL - 130
SP - 1653
EP - 1668
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -