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

Lookup NU author(s): Dr Jacqueline Stockley, Professor Craig RobsonORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Background: 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.Methods: RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and similar to 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.Results: 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).Conclusions: 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.

Publication metadata

Author(s): Rajan P, Stockley J, Sudbery IM, Fleming JT, Hedley A, Kalna G, Sims D, Ponting CP, Heger A, Robson CN, McMenemin RM, Pedley ID, Leung HY

Publication type: Article

Publication status: Published

Journal: BMC Cancer

Year: 2014

Volume: 14

Online publication date: 18/12/2014

Acceptance date: 11/12/2014

Date deposited: 20/02/2015

ISSN (electronic): 1471-2407

Publisher: BioMed Central Ltd.

URL: http://dx.doi.org/10.1186/1471-2407-14-977

DOI: 10.1186/1471-2407-14-977

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