Abstract
Background: 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. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status. Results: The 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. Conclusions: This 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.
Original language | English (US) |
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Article number | 128 |
Journal | Clinical epigenetics |
Volume | 7 |
Issue number | 1 |
DOIs | |
State | Published - Dec 12 2015 |
Keywords
- C3orf14
- CACNA1D
- CpG site
- DNA methylation
- ERG
- Epigenetics
- Epigenomic profiling
- GREM1
- Gene fusion
- KLK10
- NT5C
- PDE4D
- Prostate cancer
- RAB40C
- SEPT9
- TCGA
- TMPRSS2
- TRIB2
- Tumor tissue
- Unsupervised clustering
- mRNA expression
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Developmental Biology
- Genetics(clinical)