Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.

S Merson ; ZH Yang ; D Brewer ; D Olmos ; A Eichholz ; F McCarthy ; G Fisher ; G Kovacs ; DM Berney ; CS Foster ; +6 more... H Møller ; P Scardino ; J Cuzick ; CS Cooper ; JP Clark ; Transatlantic Prostate Group ; (2014) Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer. British journal of cancer, 110 (6). pp. 1655-1662. ISSN 0007-0920 DOI: 10.1038/bjc.2014.13
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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. CONCLUSION: 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.


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