Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer

Rajan, P. et al. (2014) Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer. BMC Cancer, 14, p. 977. (doi:10.1186/1471-2407-14-977) (PMID:25519703) (PMCID:PMC4301544)

[img]
Preview
Text
100705.pdf - Published Version
Available under License Creative Commons Attribution.

2MB

Publisher's URL: http://link.springer.com/article/10.1186%2F1471-2407-14-977

Abstract

<b>Background</b> Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post-treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers.<p></p> <b>Methods</b> RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal.<p></p> <b>Result</b> A number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015).<p></p> <b>Conclusions</b> Here we report on the first "real-time" in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stockley, Dr Jacqueline and Leung, Professor Hing and Kalna, Dr Gabriela and Rajan, Dr Prabhakar
Authors: Rajan, P., Stockley, J., Sudbery, I. M., Fleming, J. T., Hedley, A., Kalna, G., Sims, D., Ponting, C. P., Heger, A., Robson, C. N., McMenemin, R. M., Pedley, I. D., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:BMC Cancer
Publisher:BioMed Central Ltd.
ISSN:1471-2407
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in BMC Cancer 14:977
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
595221Systems analysis of RNA-binding protein function in metastic prostate cancer.Prabhakar RajanCancer Research UK (CAN-RES-UK)15339ICS - CLINICAL TRIALS RESEARCH
595222Systems analysis of RNA-binding protein function in metastic prostate cancer.Prabhakar RajanCancer Research UK (CAN-RES-UK)15339ICS - CLINICAL TRIALS RESEARCH