Abstract
BackgroundAbout half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status.ResultsThe study included 496 patients with clinically localized PCa who had a radical prostatectomy as primary treatment for PCa. Fluorescence in situ hybridization (FISH) “break-apart” assays were used to determine tumor T2E-fusion status, which showed that 266 patients (53.6 %) had T2E-positive PCa. The study showed global DNA methylation differences between tumor subtypes. A large number of differentially methylated CpG sites were identified (false-discovery rate [FDR] Q-value <0.00001; n = 27,876) and DNA methylation profiles accurately distinguished between tumor T2E subgroups. A number of top-ranked differentially methylated CpGs in genes (FDR Q-values ≤1.53E−29) were identified: C3orf14, CACNA1D, GREM1, KLK10, NT5C, PDE4D, RAB40C, SEPT9, and TRIB2, several of which had a corresponding alteration in mRNA expression. These genes may have various roles in the pathogenesis of PCa, and the calcium-channel gene CACNA1D is a known ERG-target. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings.ConclusionsThis study identified substantial differences in DNA methylation profiles of T2E-positive and T2E-negative tumors, thereby providing further evidence that different underlying oncogenic pathways characterize these molecular subtypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0161-6) contains supplementary material, which is available to authorized users.
Highlights
About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion
The present study investigated epigenome-wide DNA methylation profiles in T2E-fusion-positive versus T2Efusion-negative prostate tumors in a large populationbased cohort of 496 patients to identify differentially methylated CpG sites
Results from our study were independently validated in The Cancer Genome Atlas (TCGA)
Summary
About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. In 2005, Tomlins et al identified the fusion of two genes, ERG and TMPRSS2, as a common somatic alteration in prostate cancer (PCa) [1]. The T2E gene fusion is an early event in PCa, and fusion-positive tumors are believed to represent a distinct molecular subtype of PCa involving activation of specific oncogenic pathways [2, 3, 5,6,7,8,9,10,11,12,13]
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