Global Methylation Profiling for Risk Prediction of Prostate Cancer

Abstract

Purpose: The aim of this study was to investigate the promoter hypermethylation as diagnostic markers to detect malignant prostate cells and as prognostic markers to predict the clinical recurrence of prostate cancer.Experimental Design: DNA was isolated from prostate cancer and normal 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 ¼ 198) versus matched normal tissues (n ¼ 40), (ii) recurrence (n ¼ 123) versus nonrecurrence (n ¼ 75), (iii) clinical recurrence (n ¼ 80) versus biochemical recurrence (n ¼ 43), and (iv) systemic recurrence (n ¼ 36) versus local recurrence (n ¼ 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 significant methylation of genes in four different groups of prostate cancer tissues. The sensitivity and specificity of methylation 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. Ó2012 AACR.

Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers

“…Methylation of the RASGRF2 gene was found to be associated with prostate cancer (18). ECE1 has been implicated in prostate cancer cell invasion, in which different isoforms of the protein were found to play different roles (19).…”

Whole genome DNA methylation signature of HER2-positive breast cancer

“…In addition, HIF3A, inhibitor of HIF-mediated gene expression was also found to be hypermethylated in our study consistent with a recent report. 40 Wnt signaling pathway was affected by both hypomethylation of Bcl9, a Wnt activator 41 and hypermethylation of Wnt suppressors, such as, SOX17, APC, SFRP2, SFRP5, and DKK3. 42 Epigenetic alteration has been previously described in SOX17, APC, SFRP2, SFRP5, and DKK3 in human cancers and may result in deregulated Wnt signaling (primary references available at http://www.stanford.edu/group/nusselab/cgi-bin/wnt/).…”

Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer

“…More recent work, however, has taken advantage of technologic advances in methylation profiling that allow increasing genomic coverage to identify prognostic methylation changes in tissue samples (17,18). Previous DNA methylation profiling in prostate cell lines has also identified an increase in DNA methylation in PC3 cells versus benign prostate epithelial cells of genes repressed by histone 3, lysine 27 trimethylation (H3K27me3) via the polycomb-repressive complex 2 (PRC2; ref.…”