Correlation of ERG expression and DNA methylation biomarkers with adverse clinicopathological features of prostate cancer
Menée sur 219 échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude évalue l'association entre les niveaux de méthylation de trois gènes (CYP26A1, TBX15, HOXD3), l'expression de l'oncogène ERG et le score de Gleason
Purpose: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 novel biomarkers, and clinicopathological features of prostate cancer. Experimental Design:Immunohistochemistry for ERG protein was performed as a surrogate for TMPRSS2-ERG fusions. We analyzed methylation of CYP26A1, TBX15, and HOXD3 in 219 prostatectomy specimens using the quantitative MethyLight assay. DNA methylation was compared between ERG positive and negative cases and correlations of ERG and DNA methylation with clinicopathological features were analysed using chi-square, Spearman correlation, logistic regression, and Cox regression. Results:ERG expression varied according to Gleason pattern (almost absent in Grade 2, highest in grade 3 and lower in Grade 4/5) and showed a strong positive correlation with methylation levels of CYP26A1, TBX15, and HOXD3 (Spearman p less than 0.005). TBX15 and HOXD3 methylation were significantly associated with pathological stage, Gleason score and Gleason pattern (p less than or equal to 0.015). In multivariate regression analysis, PSA, TBX15 high methylation, and HOXD3 high methylation were significantly associated with stage (p less than 0.05), while 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 less than 0.05). Conclusions:CYP26A1, TBX15, and HOXD3 are methylation markers of prostate cancer associated with ERG expression and clinicopathological variables, suggesting that incorporation of these markers may be useful in a pre and post-treatment clinical setting.
Clinical Cancer Research , résumé, 2012