Data from Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers

<div>Abstract<p><b>Background:</b> Previously, we showed that gene suppression commonly occurs across chromosome 2q14.2 in colorectal cancer, through a process of long-range epigenetic silencing (LRES), involving a combination of DNA methylation and repressive histone modifications. We now investigate whether LRES also occurs in prostate cancer across this 4-Mb region and whether differential DNA methylation of 2q14.2 genes could provide a regional panel of prostate cancer biomarkers.</p><p><b>Methods:</b> We used highly sensitive DNA methylation headloop PCR assays that can detect 10 to 25 pg of methylated DNA with a specificity of at least 1:1,000, and chromatin immunoprecipitation assays to investigate regional epigenetic remodeling across 2q14.2 in prostate cancer, in a cohort of 195 primary prostate tumors and 90 matched normal controls.</p><p><b>Results:</b> Prostate cancer cells exhibit concordant deacetylation and methylation of histone H3 Lysine 9 (H3K9Ac and H3K9me2, respectively), and localized DNA hypermethylation of <i>EN1</i>, <i>SCTR</i>, and <i>INHBB</i> and corresponding loss of H3K27me3. <i>EN1</i> and <i>SCTR</i> were frequently methylated (65% and 53%, respectively), whereas <i>INHBB</i> was less frequently methylated.</p><p><b>Conclusions:</b> Consistent with LRES in colorectal cancer, we found regional epigenetic remodeling across 2q14.2 in prostate cancer. Concordant methylation of <i>EN1</i> and <i>SCTR</i> was able to differentiate cancer from normal (<i>P</i> < 0.0001) and improved the diagnostic specificity of <i>GSTP1</i> methylation for prostate cancer detection by 26%.</p><p><b>Impact:</b> For the first time we show that DNA methylation of <i>EN1</i> and <i>SCTR</i> promoters provide potential novel biomarkers for prostate cancer detection and in combination with <i>GSTP1</i> methylation can add increased specificity and sensitivity to improve diagnostic potential. <i>Cancer Epidemiol Biomarkers Prev; 20(1); 148–59. ©2011 AACR</i>.</p></div>