Distinct transcriptional repertoire of the androgen receptor in ETS fusion-negative prostate cancer.
Cell Line, Tumor
Computational Biology
/ methods
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Ontology
Humans
Male
Neoplasm Grading
Neoplasm Staging
Oncogene Proteins, Fusion
/ genetics
Prostatic Neoplasms
/ genetics
Proto-Oncogene Proteins c-ets
/ genetics
Receptors, Androgen
/ metabolism
Transcriptome
Journal
Prostate cancer and prostatic diseases
ISSN: 1476-5608
Titre abrégé: Prostate Cancer Prostatic Dis
Pays: England
ID NLM: 9815755
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
10
07
2018
accepted:
08
09
2018
revised:
27
08
2018
pubmed:
28
10
2018
medline:
6
2
2020
entrez:
28
10
2018
Statut:
ppublish
Résumé
Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS-) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS- PCa tumors. 10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS- (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA). Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS- and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes. ETS status influences the transcriptional repertoire of the AR, and ETS- PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.
Sections du résumé
BACKGROUND
Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS-) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS- PCa tumors.
METHODS
10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS- (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA).
RESULTS
Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS- and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes.
CONCLUSIONS
ETS status influences the transcriptional repertoire of the AR, and ETS- PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.
Identifiants
pubmed: 30367117
doi: 10.1038/s41391-018-0103-4
pii: 10.1038/s41391-018-0103-4
pmc: PMC6760558
doi:
Substances chimiques
Oncogene Proteins, Fusion
0
Proto-Oncogene Proteins c-ets
0
Receptors, Androgen
0
Banques de données
ClinicalTrials.gov
['NCT02609269']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
292-302Subventions
Organisme : NCI NIH HHS
ID : P20 CA233255
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Références
MAGMA. 2000 Jul;10(3):153-9
pubmed: 10873205
J Biol Chem. 2002 May 3;277(18):16189-201
pubmed: 11839751
Prostate. 2002 Mar 1;50(4):252-61
pubmed: 11870804
Oncogene. 2005 May 26;24(23):3847-52
pubmed: 15750627
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Science. 2005 Oct 28;310(5748):644-8
pubmed: 16254181
Biostatistics. 2007 Jan;8(1):118-27
pubmed: 16632515
Nat Genet. 2007 Jan;39(1):41-51
pubmed: 17173048
Nature. 2007 Aug 2;448(7153):595-9
pubmed: 17671502
Oncogene. 2008 Sep 11;27(40):5348-53
pubmed: 18542058
Curr Drug Targets. 2008 Jul;9(7):571-80
pubmed: 18673243
Clin Cancer Res. 2008 Aug 1;14(15):4719-25
pubmed: 18676740
Clin Cancer Res. 2009 Jul 15;15(14):4706-11
pubmed: 19584163
Curr Genomics. 2009 Mar;10(1):18-25
pubmed: 19721807
Science. 2009 Nov 27;326(5957):1230
pubmed: 19933109
Cancer Cell. 2010 May 18;17(5):443-54
pubmed: 20478527
PLoS One. 2010 May 10;5(5):e10547
pubmed: 20479932
Prostate. 2011 Apr;71(5):489-97
pubmed: 20878952
J Pharmacol Exp Ther. 2011 Feb;336(2):344-55
pubmed: 21030485
Nature. 2011 Feb 10;470(7333):214-20
pubmed: 21307934
EMBO J. 2011 May 20;30(13):2719-33
pubmed: 21602788
PLoS Comput Biol. 2011 Oct;7(10):e1002240
pubmed: 22028643
Genes Chromosomes Cancer. 2012 Mar;51(3):240-9
pubmed: 22081504
BMC Cancer. 2011 Dec 05;11:507
pubmed: 22142399
Cancer Cell. 2013 Jan 14;23(1):35-47
pubmed: 23260764
Cancer Cell. 2013 Feb 11;23(2):159-70
pubmed: 23410972
Clin Cancer Res. 2013 Jul 1;19(13):3450-61
pubmed: 23549870
Neoplasia. 2013 May;15(5):491-501
pubmed: 23633921
Future Oncol. 2013 Jun;9(6):899-907
pubmed: 23718310
Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17778-83
pubmed: 24128763
Cell Commun Signal. 2014 Sep 25;12:61
pubmed: 25248616
J Clin Oncol. 2015 Sep 1;33(25):2789-96
pubmed: 26195723
Nat Genet. 2015 Nov;47(11):1346-51
pubmed: 26457646
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
Nat Commun. 2015 Dec 04;6:8971
pubmed: 26634437
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Eur J Cancer. 2016 Apr;57:39-49
pubmed: 26854828
Sci Rep. 2016 Feb 11;6:20984
pubmed: 26865432
J Steroid Biochem Mol Biol. 2017 Feb;166:1-15
pubmed: 27117390
Clin Exp Pharmacol Physiol. 2017 Jun;44(6):700-708
pubmed: 28261855
Int J Genomics. 2017;2017:2354564
pubmed: 28265563
J Mol Diagn. 2017 May;19(3):475-484
pubmed: 28341589
Oncotarget. 2017 Feb 7;8(31):50804-50813
pubmed: 28881605