title: Correlation of ERG expression and DNA methylation biomarkers with adverse clinicopathologic features of prostate cancer.
abstract: OBJECTIVE
  Fusion of the TMPRSS2 gene with the ERG oncogene and aberrant DNA methylation patterns are commonly found in prostate cancer. The aim of this study was to analyze the relationship between ERG expression, DNA methylation of three biomarkers, and clinicopathologic features of prostate cancer.
  
  
  METHODS
  Immunohistochemistry for ERG protein was conducted as a surrogate for TMPRSS2-ERG fusions. We analyzed methylation of CYP26A1, TBX15, and HOXD3 in 219 prostatectomy specimens by the quantitative MethyLight assay. DNA methylation was compared between ERG-positive and -negative cases and correlations of ERG and DNA methylation with clinicopathologic features were analyzed using χ(2), Spearman correlation, logistic regression, and Cox regression.
  
  
  RESULTS
  ERG expression varied according to Gleason pattern (almost absent in pattern II, highest in pattern III, and lower in pattern IV/V) and showed a strong positive correlation with methylation levels of CYP26A1, TBX15, and HOXD3 (Spearman P < 0.005). TBX15 and HOXD3 methylation were significantly associated with pathologic stage, Gleason score, and Gleason pattern (P ≤ 0.015). In multivariate regression analysis, PSA, TBX15 high methylation, and HOXD3 high methylation were significantly associated with stage (P < 0.05), whereas ERG expression was negatively correlated with Gleason score (P = 0.003). In univariate time-to-recurrence analysis, a combination of HOXD3/TBX15 high methylation predicted recurrence in ERG-positive and -negative cases (P < 0.05).
  
  
  CONCLUSIONS
  CYP26A1, TBX15, and HOXD3 are methylation markers of prostate cancer associated with ERG expression and clinicopathologic variables, suggesting that incorporation of these markers may be useful in a pre- and posttreatment clinical setting.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Ken
authors.initials: K
authors.lastname: Kron
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.forename: Dominique
authors.initials: D
authors.lastname: Trudel
authors.forename: Vaijayanti
authors.initials: V
authors.lastname: Pethe
authors.forename: John
authors.initials: J
authors.lastname: Trachtenberg
authors.forename: Neil
authors.initials: N
authors.lastname: Fleshner
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D019175:DNA Methylation; D018572:Disease-Free Survival; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D017430:Prostate-Specific Antigen / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D000072516:Retinoic Acid 4-Hydroxylase; D012697:Serine Endopeptidases / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
chemical_list: D014408:Biomarkers, Tumor; C072312:ERG protein, human; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D020825:T-Box Domain Proteins; C523795:TBX15 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C073547:HOXA4 protein, human; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen