MYC DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

Kathryn Hughes Barry,Ashley Cellini,Jing Yin,Jianxin Shi,Søren M Bentzen,Arif Hussain,Sonja I Berndt,Kareshma Mohanty,Gary Rose,Difei Wang,Ann Meyer,Yuji Zhang,Nicholas Ambulos,Liying Yan,Kimberly Clark,Allen Burke,Patricia A Erickson,Matthew Poulin

doi:10.3390/genes12010012

Abstract

Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3′ UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: −14.74 to −0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; p-value = 9.4 × 10−4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.

Highlights

Chromosome 8q24 has been established as an important region in the genetic susceptibility to prostate cancer [1,2,3,4,5,6,7,8,9,10,11], among men of African ancestry, where additional susceptibility single nucleotide polymorphisms (SNPs) have been discovered that are monomorphic in other populations [10] and explain a greater proportion of familial risk [12]
Center who had available MYC DNA methylation data for analysis, age at radical prostatectomy ranged from 42–75 years, with a median age of 58 years; the distribution of age at diagnosis was similar to the age at surgery (Table 1)
Based on the importance of the 8q region and the MYC gene in prostate carcinogenesis/progression [13,40], we investigated the role of MYC DNA methylation in prostate tumor tissue from African American and Caucasian prostate cancer patients who underwent radical prostatectomy at the University of Maryland Medical Center

Summary

Introduction

Chromosome 8q24 has been established as an important region in the genetic susceptibility to prostate cancer [1,2,3,4,5,6,7,8,9,10,11], among men of African ancestry, where additional susceptibility single nucleotide polymorphisms (SNPs) have been discovered that are monomorphic in other populations [10] and explain a greater proportion of familial risk [12]. The 8q24 locus has been traditionally described as a gene desert, with the nearest prostate cancer susceptibility SNP located about 200 kb upstream of the oncogene. This terminology is somewhat misleading, since there are several other genes and non-coding RNAs (ncRNAs) located at 8q24. MYC is commonly overexpressed in prostate tumor tissue and has long been thought to play a role in prostate cancer, and with regard to prostate cancer progression [13]

Methods

Results

Conclusion