Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.
BACKGROUND
Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy.


METHODS
A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation.


RESULTS
Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival.


CONCLUSIONS
Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.
Molecular Carcinogenesis, Institute of Cancer Research, Male Urological Cancer Research Centre, Surrey, UK.
S
S
Merson
The Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, St Bartholomew's Medical School, Queen Mary, University of London, London, UK.
Z H
ZH
Yang
1] Molecular Carcinogenesis, Institute of Cancer Research, Male Urological Cancer Research Centre, Surrey, UK [2] Department of Cancer Genetics, University of East Anglia, Norwich, UK.
D
D
Brewer
Prostate Cancer Research, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 28029 Madrid, Spain.
D
D
Olmos
Molecular Carcinogenesis, Institute of Cancer Research, Male Urological Cancer Research Centre, Surrey, UK.
A
A
Eichholz
Molecular Carcinogenesis, Institute of Cancer Research, Male Urological Cancer Research Centre, Surrey, UK.
F
F
McCarthy
The Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, St Bartholomew's Medical School, Queen Mary, University of London, London, UK.
G
G
Fisher
Laboratory of Molecular Oncology, Medical Faculty, Ruprecht-Karls-Universitat, Heidelberg, Germany.
G
G
Kovacs
Department of Molecular Oncology, Barts Cancer Institute, Charterhouse Square, London, UK.
D M
DM
Berney
Molecular Pathology Laboratory, Liverpool University, Liverpool, UK and HCA Laboratories, London, UK.
C S
CS
Foster
1] The Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, St Bartholomew's Medical School, Queen Mary, University of London, London, UK [2] King's College London, Cancer Epidemiology and Population Health, London, UK.
H
H
Møller
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
P
P
Scardino
The Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, St Bartholomew's Medical School, Queen Mary, University of London, London, UK.
J
J
Cuzick
Department of Cancer Genetics, University of East Anglia, Norwich, UK.
C S
CS
Cooper
Department of Cancer Genetics, University of East Anglia, Norwich, UK.
J P
JP
Clark
D000368:Aged; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008297:Male; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
C410798:AR protein, human; D011944:Receptors, Androgen