Molecular Diagnostics

BJC Open article

British Journal of Cancer (2010) 102, 570–576. doi:10.1038/sj.bjc.6605519 www.bjcancer.com
Published online 12 January 2010

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

B G Barwick1,8, M Abramovitz2,8,9, M Kodani1,10, C S Moreno1,3,6, R Nam4, W Tang1, M Bouzyk1,7, A Seth5 and B Leyland-Jones1,6

  1. 1Emory Biomarker Service Center, Emory University, 1365C Clifton Road, NE, Atlanta, GA 30322, USA
  2. 2VM Institute of Research, 2020 University St., Suite 2040, Montreal, Quebec, Canada H3A 2A5
  3. 3Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
  4. 4Divisions of Urology and Surgical Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  5. 5Sunnybrook Research Institute, University of Toronto, Ontario, Canada
  6. 6Robert W Woodruff Health Sciences Center, Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, NE, Suite 4014, Atlanta, GA 30322, USA
  7. 7Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA

Correspondence: Dr B Leyland-Jones, E-mail: Leyland@emory.edu; Dr M Abramovitz, E-mail: mark.abramovitz@mail.mcgill.ca

8These authors contributed equally to this work.

9Current address: Departments of Pathology and Oncology, Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, Quebec, Canada H3T 1E2.

10Current address: Centers for Disease Control and Prevention, 1600 Clifton Road, NE, Atlanta, GA 30333, USA.

Revised 23 November 2009; Accepted 1 December 2009
Advance online publication 12 January 2010

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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.

Keywords:

prostate cancer; TMPRSS2–ERG fusion; DASL; microarray; recurrence

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