Neuroendocrine differentiation in usual-type prostatic adenocarcinoma: Molecular characterization and clinical significance.
Adenocarcinoma
/ genetics
Carcinoma, Small Cell
/ genetics
Cell Differentiation
/ physiology
Cohort Studies
Humans
Immunohistochemistry
Male
Middle Aged
Neuroendocrine Cells
/ metabolism
Neuroendocrine Tumors
/ genetics
PTEN Phosphohydrolase
/ genetics
Prostatic Neoplasms
/ genetics
Prostatic Neoplasms, Castration-Resistant
/ genetics
Receptors, Androgen
/ biosynthesis
Retinoblastoma Binding Proteins
/ genetics
Retrospective Studies
Signal Transduction
Tumor Suppressor Protein p53
/ genetics
Ubiquitin-Protein Ligases
/ genetics
androgen receptor
neuroendocrine differentiation
paneth cells
prostate adenocarcinoma
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
25
05
2020
accepted:
14
06
2020
pubmed:
11
7
2020
medline:
29
9
2020
entrez:
11
7
2020
Statut:
ppublish
Résumé
Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.
Sections du résumé
BACKGROUND
Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain.
METHODS
We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55).
RESULTS
Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9).
CONCLUSION
NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.
Identifiants
pubmed: 32649013
doi: 10.1002/pros.24035
pmc: PMC9524879
mid: NIHMS1620032
doi:
Substances chimiques
AR protein, human
0
RB1 protein, human
0
Receptors, Androgen
0
Retinoblastoma Binding Proteins
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1012-1023Subventions
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA058236
Pays : United States
Organisme : NCI NIH HHS
ID : P50CA58236
Pays : United States
Organisme : NCI NIH HHS
ID : 5P30CA006973-52
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals LLC.
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