Imaging, Diagnosis, Prognosis Global Methylation Profiling for Risk Prediction of Prostate Cancer

Purpose:The aimof this studywas to investigate thepromoter hypermethylation asdiagnosticmarkers to detectmalignant prostate cells and as prognosticmarkers to predict the clinical recurrence of prostate cancer. ExperimentalDesign:DNAwas isolated fromprostate cancer andnormal adjacent tissues. After bisulfite conversion, methylation of 14,495 genes was evaluated using the Methylation27 microarrays in 238 prostate tissues. We analyzed methylation profiles in four different groups: (i) tumor (n 1⁄4 198) versus matched normal tissues (n 1⁄4 40), (ii) recurrence (n 1⁄4 123) versus nonrecurrence (n 1⁄4 75), (iii) clinical recurrence (n 1⁄4 80) versus biochemical recurrence (n 1⁄4 43), and (iv) systemic recurrence (n 1⁄4 36) versus local recurrence (n 1⁄4 44). Group 1, 2, 3, and 4 genes signifying biomarkers for diagnosis, prediction of recurrence, clinical recurrence, and systemic progression were determined. Univariate and multivariate analyses were conducted to predict risk of recurrence. We validated the methylation of genes in 20 independent tissues representing each group by pyrosequencing. Results:Microarray analysis revealed significantmethylation of genes in four different groups of prostate cancer tissues. The sensitivity and specificity ofmethylation for 25 genes from 1, 2, and 4 groups and 7 from group 3 were shown. Validation of genes by pyrosequencing from group 1 (GSTP1, HIF3A, HAAO, and RARb), group 2 (CRIP1, FLNC, RASGRF2, RUNX3, and HS3ST2), group 3 (PHLDA3, RASGRF2, and TNFRSF10D), and group 4 (BCL11B, POU3F3, and RASGRF2) confirmed the microarray results. Conclusions: Our study provides a global assessment of DNA methylation in prostate cancer and identifies the significance of genes as diagnostic and progression biomarkers of prostate cancer. Clin Cancer Res; 18(10); 2882–95. 2012 AACR.