Prostate cancer genes associated with TMPRSS2-ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

• Type of Material: Article
• Authors: BG Barwick, Emory University; M Abramovitz, VM Institute of Research; M Kodani, Emory University; Carlos S Moreno, Emory University; R Nam, Sunnybrook Health Sciences Centre; W Tang, Emory University; M Bouzyk, Emory University; A Seth, University of Toronto; B Leyland-Jones, Emory University
• Language: English
• Date: 2010-02-02
• Publisher: Cancer Research UK
• Publication Version: Final Published Version
• Copyright Statement: © 2010 Cancer Research UK.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1038/sj.bjc.6605519
• Title of Journal or Parent Work: British Journal of Cancer
• ISSN: 0007-0920
• Volume: 102
• Issue: 3
• Start Page: 570
• End Page: 576
• Grant/Funding Information: This research is funded in part by the Canadian Cancer Society (Grant no. 019038).
• Keywords: TMPRSS2-ERG fusion; FAMILY; recurrence; Oncology; PROGRESSION; PSA; MUC1; THERAPY; PTEN; microarray; BIOPSY; Science & Technology; DELETIONS; prostate cancer; DASL; EXPRESSION; FISH ANALYSIS; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Background:Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers.Methods:RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) 5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value 0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings.Results:In the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR 0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2-ERG fusion status.Conclusions: TMPRSS2-ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation.