Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors

Milan S. Geybels, Joshi J. Alumkal, Manuel Luedeke, Antje Rinckleb, Shanshan Zhao, Irene M. Shui, Marina Bibikova, Brandy Klotzle, Piet A. van den Brandt, Elaine A. Ostrander, Jian Bing Fan, Ziding Feng, Christiane Maier, Janet L. Stanford

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    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 languageEnglish (US)
    Article number128
    JournalClinical epigenetics
    Volume7
    Issue number1
    DOIs
    StatePublished - Dec 12 2015

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    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)

    Cite this

    Geybels, M. S., Alumkal, J. J., Luedeke, M., Rinckleb, A., Zhao, S., Shui, I. M., Bibikova, M., Klotzle, B., van den Brandt, P. A., Ostrander, E. A., Fan, J. B., Feng, Z., Maier, C., & Stanford, J. L. (2015). Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors. Clinical epigenetics, 7(1), [128]. https://doi.org/10.1186/s13148-015-0161-6