Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-977) contains supplementary material, which is available to authorized users.
Highlights
Chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant
Genomic rearrangements involving ETS-family transcription factors are implicated in PCa with the most common gene fusion product TMPRSS2/ERG reported in >50% cases [31]
To the best of our knowledge, our study is the first “real time” in vivo RNA sequencing (RNA-Seq)-based transcriptome analysis of clinical PCa from pre- and post-treatment Transrectal ultrasound (TRUSS)-guided biopsies of patients treated with docetaxel chemotherapy plus androgen deprivation therapy (ADT)
Summary
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. The mainstay of treatment for “incurable” locally-advanced/ metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT) [1], after ~2-3 years the disease becomes castration-resistant (CRPCa). Trials demonstrated an overall median ~2-3 month survival advantage for docetaxel-based therapies over standard treatments for CRPCa [3,4], supporting its recommendation as first-line standard of care for CRPCa [1]. Docetaxel plus ADT have been found to confer no statistically-significant survival advantage over ADT alone for non-CRPCa (i.e. hormone-naïve disease), despite an improvement in clinical and biochemical progression-free survival [7]
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