Supplementary Figures 1-5 from Genome-wide DNA Methylation Events in <i>TMPRSS2–ERG</i> Fusion-Negative Prostate Cancers Implicate an EZH2-Dependent Mechanism with <i>miR-26a</i> Hypermethylation
Stefan T. BörnoAxel FischerMartin KerickMaria FälthMark LaibleJan C. BraseRuprecht KunerAndreas DahlChristina GrimmBehnam SayanjaliMelanie IsauChristina RöhrAndrea WunderlichBernd TimmermannRainer ClausChristoph PlassMarkus GraefenRonald SimonFrancesca DemichelisMark A. RubinGuido SauterThorsten SchlommHolger SültmannHans LehrachMichal R. Schweiger
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<p>PDF file - 947K, Supplementary Fig. S1. Differential methylations in PCa validated by BS-MS experiments. Supplementary Fig. S2. DNA-Methylomes of prostate cancer differ significantly from normal tissues. Supplementary Fig. S3. Global differences in DNA methylation patterns between tumor, normal, FUS+ and FUS- samples. Supplementary Fig. S4 Patientwise patterns of promoter hypermethylation and corresponding gene expression of EZH2 target genes. Supplementary Fig. S5 Methylation of the miRNA-26a genomic region</p>Keywords:
TMPRSS2
The gene fusions between transmembrane protease serine 2 (TMPRSS2) and E26 (ETS) transcription factors are present in over 50% of patients with prostate cancer. TMPRSS2-ERG is the most common gene fusion type. The ERG overexpression induced by TMPRSS2-ERG gene fusion contributes to the development of prostate cancer. Both androgen receptor binding and genotoxic stress induce chromosomal proximity and TMPRSS2-ETS gene fusions. TMPRSS2-ERG gene fusion functions as a biomarker for prostate cancer, which can be easily detected in urine. This review focuses on the characteristics, oncogenic and rearranged mechanism, and clinical application of TMPRSS2-ETS gene fusions.
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TMPRSS2-ERG fusion is the most common subtype of gene fusions in prostate cancer.Interacting with AR,PARP1and DNA-PKcs,NF-κB and CRISP3,TMPRSS2-ERG fusion gene leads to the genesis of prostate cancer.By fluorescence in situ hybridization and immunohistochemistry,TMPRSS2-ERG fusion gene and the related protein have a higher positive rate in specimen of prostate cancer.Urinary detection of TMPRSS2-ERG fusion gene also has a higher specificity and positive predictive value.
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DNA methylation measured in white blood cell DNA is increasingly being used as in studies of cancer susceptibility. However, little is known about the correlation between different assays to measure global methylation and whether the source of DNA matters when examining methylation profiles in different blood cell types. Using information from 620 women, 217 and 403 women with DNA available from granulocytes (Gran), and total white blood cells (WBC), respectively, and 48 women with DNA available from four different sources (WBC, Gran, mononuclear (MN), and lymphoblastoid cell lines (LCL)), we compared DNA methylation for three repetitive elements (LINE1, Sat2, Alu) by MethyLight, luminometric methylation assay (LUMA), and [3H]-methyl acceptance assay. For four of the five assays, DNA methylation levels measured in Gran were not correlated with methylation in LBC, MN, or WBC; the exception was Sat2. DNA methylation in LCL was correlated with methylation in MN and WBC for the [3H]-methyl acceptance, LINE1, and Alu assays. Methylation in MN was correlated with methylation in WBC for the [3H]-methyl acceptance and LUMA assays. When we compared the five assays to each other by source of DNA, we observed statistically significant positive correlations ranging from 0.3-0.7 for each cell type with one exception (Sat2 and Alu in MN). . Among the 620 women stratified by DNA source, correlations among assays were highest for the three repetitive elements (range 0.39-0.64). Results from the LUMA assay were modestly correlated with LINE1 (0.18-0.20). These results suggest that both assay and source of DNA are critical components in the interpretation of global DNA methylation patterns from WBC.
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A unique fusion between the TMPRSS2 gene and the Ets genes ERG,ETV1、ETV4 or ETV5 has been described in prostate cancer, TMPRSS2-ERG is the most high frequency of all. Until now more than 20 kinds of TMPRSS2- ERG hybrid transcripts are found, and they encode 9 kinds of proteins. Deletion is the main mechanism of fusion. Fusion gene can be used to make a diagnosis of prostate cancer , direct clinical medication , then fusion type, fusion number and transcriptive type are also associated with prognosis of dis-ease. So, besides of serum PSA, Gleason score, TMPRSS2- ERG is expected to be another important predicator of prognosis.
Key words:
Prostatic neoplasms; Gene fusion; In situ hybridization, fluorescence; Serine endopepti-dases; Ets
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The Ets-related gene fusions are among the most common molecular alterations in prostate cancer (PCa) and are detected in more than 50 % of PCas. Transmembrane protease serine 2 and Ets-related gene fusion (TMPRSS2-ERG) is the most frequently identified chimeric gene and has been associated with undifferentiated and invasive phenotypes. TMPRSS2-ERG has also been detected in prostate intraepithelial neoplasia (PIN) lesions and more rarely in benign prostatic hyperplasia (BPH) regions mainly in PCa-bearing glands. The possibility that the fusion TMPRSS2-ERG may be present in BPH samples in the absence of apparent PCa was addressed. Out of 115 BPH samples, three were found positive employing RT-PCR. The presence of the fusion gene was confirmed by FISH for these samples, and an additional four samples were found to carry the TMPRSS2-ERG fusion out of 43 tested by the later approach. The presence of the TMPRSS2-ERG fusion did not result in altered expression of 12 putative downstream targets. These findings indicate that TMPRSS2-ERG may or may not lead to PCa development.
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This study investigated differences in prevalence of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) and ETS transcription factor family member, v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion gene (TMPRSS2-ERG fusions) in clinically localized prostate cancer Japanese and German patients.A total of 105 specimens, including 69 Japanese and 36 German patients, were collected.The status of TMPRSS2-ERG fusion was determined by fluorescence in situ hybridization, and correlations of the TMPRSS2-ERG fusion with clinicopathological characteristics and immunohistochemistry were studied.Gene fusions were identified in 20% (14/69) of Japanese and 53% (19/36) of German patients (P < 0.001).The difference in the type of gene fusion between the two ethnic groups was statistically significant (P=0.024).Overexpression of ERG protein was significantly associated with gene fusion.Biochemical recurrence was significantly higher in patients with ERG overexpression than in those without, and not related to TMPRSS2-ERG fusion status.Interestingly, two types of gene fusions (deletion and increase of copy number) were significantly associated with increased p53 expression (P = 0.005).Association of specific gene fusions harboring higher genomic alterations with p53 expression levels suggests that p53 mutation might drive more aggressive rearrangements of TMPRSS2-ERG fusion in prostate cancer.
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Abstract Fusion genes play important roles in tumorigenesis. The identification of the high-frequency TMPRSS2 fusion with ERG and other ETS family genes in prostate cancer highlights the importance of fusion genes in solid tumor development and progression. However, the mechanisms leading to these fusions are unclear. We investigated whether androgen, through stimulating its receptor, could promote spatial genome reorganization and contribute to the generation of the TMPRSS2:ERG fusion. We show that treatment with androgen can induce the TMPRSS2:ERG fusion in both malignant and nonmalignant prostate epithelial cells. Although the fusion could be detected in malignant cells following 24-hour treatment, prolonged exposure to androgen was required to detect the fusion transcript in nonmalignant cells. We associated the fusion incidence with genetic factors, including androgen-induced gene proximity, androgen receptor exon1 CAG repeat length and expression of the PIWIL1 gene. This study demonstrates that fusions can be induced prior to malignant transformation and generation of the fusion is associated with both gene proximity and loss of the ability to prevent double-strand breaks. Cancer Res; 70(23); 9544–8. ©2010 AACR.
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