Clinical Epigenetics | |
Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors | |
Janet L. Stanford8  Christiane Maier7  Ziding Feng9  Jian-Bing Fan1  Elaine A. Ostrander5  Piet A. van den Brandt6  Brandy Klotzle1  Marina Bibikova1  Irene M. Shui4  Shanshan Zhao2  Antje Rinckleb7  Manuel Luedeke7  Joshi J. Alumkal3  Milan S. Geybels6  | |
[1] Illumina, Inc., San Diego, CA, USA;Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA;Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA;Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands;Institute of Human Genetics and Department of Urology, Faculty of Medicine, University of Ulm, Ulm, Germany;Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA;MD Anderson Cancer Center, Houston, TX, USA | |
关键词: TCGA; TRIB2; SEPT9; RAB40C; PDE4D; NT5C; KLK10; GREM1; CACNA1D; C3orf14; mRNA expression; Unsupervised clustering; Tumor tissue; ERG; TMPRSS2; Gene fusion; Prostate cancer; Epigenomic profiling; Epigenetics; CpG site; DNA methylation; | |
Others : 1235005 DOI : 10.1186/s13148-015-0161-6 |
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received in 2015-09-11, accepted in 2015-12-03, 发布年份 2015 |
【 摘 要 】
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.
【 授权许可】
2015 Geybels et al.
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