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

Research Article

Gabriela Kalna¹  Janis T Fleming¹  Ann Hedley¹  Hing Y Leung²  Jacqueline Stockley³  Prabhakar Rajan³  Ian M Sudbery⁴  Chris P Ponting⁴  Andreas Heger⁴  David Sims⁴  Craig N Robson⁵  Rhona M McMenemin⁶  Ian D Pedley⁶ 

[1] CR-UK Beatson Institute, Bearsden, UK;Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, G61 1BD, Bearsden, UK;Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK;MRC Functional Genomics Unit, Oxford, UK;Newcastle University, Newcastle, UK;Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK;

关键词: Prostate cancer;    Androgen deprivation therapy;    Biomarkers;    Docetaxel;    Cell cycle;   

DOI  :  10.1186/1471-2407-14-977

 received in 2014-08-26, accepted in 2014-12-11,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAlthough 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.MethodsRNA 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.ResultsA 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).ConclusionsHere 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.

【 授权许可】

CC BY   
© Rajan et al.; licensee BioMed Central. 2014