jueves, 25 de marzo de 2010

Prostate Cancer Genes Associated With TMPRSS2-ERG Gene Fusion And Prognostic Of Biochemical Recurrence In Multiple Cohorts

Prostate Cancer Genes Associated With TMPRSS2-ERG Gene Fusion And Prognostic Of Biochemical Recurrence In Multiple Cohorts
Main Category: Prostate / Prostate Cancer
Also Included In: Cancer / Oncology; Genetics
Article Date: 22 Mar 2010 - 1:00 PDT

UroToday.com - Fusion of the promoter/enhancer region of the androgen-responsive prostate specific serine protease 2-encoding gene, TMPRSS2 to the ETS variant 1 gene (ETV1) occurs uniquely in prostate cancer (CaP). Approximately 40-50% of CaP cases demonstrate a gene fusion. The most common fusion variant is a recombination between exon 1 of TMPRSS2 and exon 4 of ERG, designated T1/E4. This fusion may account for up to 85% of reported fusions. A previous study isolated RNA from 165 patients' radical prostatectomy specimens and 81 (49%) were found to have a gene fusion. The patients with the fusion had a higher risk of biochemical recurrence (58%) at 5 years than those without detectable fusion transcripts. In this study, the RNA from 139 of these 165 patients was characterized for the expression of 502 cancer-related genes using the cDNA-mediated, annealing, selection, extension and ligation (DASL) assay. The goal was to identify CaP genes associated with the TMPRSS2-ERG gene fusion that would be prognostic of biochemical recurrence.

The DASL assay was performed on a 502-gene Human Cancer Panel using 200ng of input RNA. Differential mRNA expression of TMPRSS2-ERG T1/E4 gene fusion-positive vs. fusion-negative was assessed using significance analysis of microarrays. The results demonstrate high assay reproducibility. There were 69-fusion positive patients and 70 fusion-negative patients. This cohort was also compared to a cohort of 455 Swedish patients and 596 patients from Minnesota. Fifteen genes were found to be differentially regulated in the TMPRSS2-ERG gene fusion tumors; nine were upregulated, and 6 were downregulated. ERG was uniquely the most significant differentially regulated transcript in TMPRSS2-ERG fusion-positive tumors. Upregulated genes were often involved with mismatch base repair and histone deacetylation functions. Downregulated genes were related to insulin-like growth factor and Jak-Stat signaling pathways. Analysis of genes with biochemical recurrence in the 139 patient cohort identified 16 genes associated with recurrence and 11 genes associated with non-recurrence. Using the Minnesota cohort, 5 genes were validated that associated with recurrence and 4 genes validated with non-recurrence. Genes involved with cell-matrix adhesion were involved with both recurrence and non-recurrence. A nine-gene panel prognostic of recurrence was used to build a recurrence score that was then combined with the Gleason score and TMPRSS2-ERG fusion status and found to correlate highly with recurrence.

Barwick BG, Abramovitz M, Kodani M, Moreno CS, Nam R, Tang W, Bouzyk M, Seth A, Leyland-Jones B

Br J Cancer. 2010 Feb 2;102(3):570-6


Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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