Reduction in expression of the benign AR transcriptome is a hallmark of localised prostate cancer progression.
BACKGROUND
Despite the importance of androgen receptor (AR) signalling to prostate cancer development, little is known about how this signalling pathway changes with increasing grade and stage of the disease.


OBJECTIVE
To explore changes in the normal AR transcriptome in localised prostate cancer, and its relation to adverse pathological features and disease recurrence.


METHODS
Publically accessible human prostate cancer expression arrays as well as RNA sequencing data from the prostate TCGA. Tumour associated PSA and PSAD were calculated for a large cohort of men (n=1108) undergoing prostatectomy.


METHODS
We performed a meta-analysis of the expression of an androgen-regulated gene set across datasets using Oncomine. Differential expression of selected genes in the prostate TCGA database was probed using the edgeR Bioconductor package. Changes in tumour PSA density with stage and grade were assessed by Student's t-test, and its association with biochemical recurrence explored by Kaplan-Meier curves and Cox regression.


RESULTS
Meta-analysis revealed a systematic decline in the expression of a previously identified benign prostate androgen-regulated gene set with increasing tumour grade, reaching significance in nine of 25 genes tested despite increasing AR expression. These results were confirmed in a large independent dataset from the TCGA. At the protein level, when serum PSA was corrected for tumour volume, significantly lower levels were observed with increasing tumour grade and stage, and predicted disease recurrence.


CONCLUSIONS
Lower PSA secretion-per-tumour-volume is associated with increasing grade and stage of prostate cancer, has prognostic relevance, and reflects a systematic perturbation of androgen signalling.
Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.|Department of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.|Department of Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.
Ryan
R
Stuchbery
NICTA Victoria Research Laboratory, University of Melbourne, Parkville, VIC, Australia.
Geoff
G
Macintyre
NICTA Victoria Research Laboratory, University of Melbourne, Parkville, VIC, Australia.
Marek
M
Cmero
Department of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.|Department of Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.
Laurence M
LM
Harewood
Department of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.|Department of Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.
Justin S
JS
Peters
Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.|Department of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.|Department of Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.
Anthony J
AJ
Costello
Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.|Department of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.|Department of Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.
Christopher M
CM
Hovens
Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.|Department of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.|Department of Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.
Niall M
NM
Corcoran
D006801:Humans; D008297:Male; D015331:Cohort Studies; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery; D011944:Receptors, Androgen / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics
D017430:Prostate-Specific Antigen; D011944:Receptors, Androgen
PSA screening; androgen signalling; prognostics; prostate cancer