Abstract 2781: Novel putative diagnostic methylation biomarkers for prostate cancer identified by whole genome DNA methylation profiling
Authors: Chakraborty Arup Ratan , Hlavin Bell Erica , Kriste Simon , Drendel Vanessa , McElRoy Joseph , Werner Martin , Grosu Anca , Chakravarti Arnab 
Published: July 2016

BACKGROUND

Aberrant patterns of DNA methylation is a typical hallmark of cancer. Several studies have reported DNA hypermethylation of a significant number of genes in various malignancies. This suggests a role of hypermethylation in the initiation and progression of cancer. In this study, we investigated genome-wide alterations in DNA methylation in prostate cancer (PCa). We compared alterations between tumor (Tu) and adjacent epithelial (Ep) tissues in order to identify hypermethylated genes in promoter regions associated with initiation and progression of prostate cancer.

METHODS

The study included 33 tumor samples including 21 paired Tu and Ep samples from 21 radical prostatectomy patients. Genomic DNA was isolated from FFPE tissue blocks. Genome-wide DNA methylation profiling was performed using the Infinium Illumina 450K array. A mixed linear model, with a random effect for patient, main effect of tissue, and covariate of array batch, was employed to identify probes that differed in methylation between tissue types. Multiple comparison adjustment was performed using the FDR (false discovery rate) method.

RESULTS

In total, 8791 hypermethylated CpG sites in the promoter regions were identified in Tu versus Ep tissue with FDR adjusted P &lt;0.05. Hypermethylation status of our top-ranked hypermethylated genes (with an estimated mean absolute difference 0.3 or greater) between tumor and epithelial tissue was also observed in publicly available methylation data in PCa. To find out if promoter hypermethylation was associated with the regulation of gene expression, we analyzed gene expression of the 20 top-ranked hypermethylated genes using publicly available mRNA expression data in PCa. Several genes exhibited reduced expression in PCa samples. Similar observation was also noted in in vitro studies as significant (P &lt;0.05) increase in gene expression following 5-Azacytidine treatment was detected only in PCa cell lines but not in normal prostate cell line.

CONCLUSIONS

This study identified promoter hypermethylation of several genes in PCa. These newly identified hypermethylated genes are potential biomarker candidates for PCa diagnosis. Currently we are evaluating the functional significance of these hypermethylated genes in prostate cancer.

This work was supported by R01CA108633 (To AC), 1RC2CA148190 (To AC) U10CA180850-01 (To AC), 1R01CA169368 (To AC) from the National Cancer Institute (NCI), Brain Tumor Funders Collaborative Grant (To AC), Ohio State University Comprehensive Cancer Center Award (To AC).

Citation Format: Arup Ratan Chakraborty, Erica Hlavin Bell, Simon Kriste, Vanessa Drendel, Joseph McElRoy, Martin Werner, Anca Grosu, Arnab Chakravarti. Novel putative diagnostic methylation biomarkers for prostate cancer identified by whole genome DNA methylation profiling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2781.