Identification of novel DNA-methylated genes that correlate with human prostate cancer and high-grade prostatic intraepithelial neoplasia

Prostate cancer (PCa) harbors a myriad of genomic and epigenetic defects. Cytosine methylation of CpG-rich promoter DNA is an important mechanism of epigenetic gene inactivation in PCa.

There is considerable amount of data to suggest that DNA methylation-based biomarkers may be useful for the early detection and diagnosis of PCa. In addition, candidate gene-based studies

have shown an association between specific gene methylation and alterations and clinicopathologic indicators of poor prognosis in PCa.

To more comprehensively identify DNA methylation alterations in PCa initiation and progression, we examined the methylation status of 485 577 CpG sites from regions with a broad spectrum of

CpG densities, interrogating both gene-associated and non-associated regions using the recently developed Illumina 450K methylation platform.

In all, we selected 33 promoter-associated novel CpG sites that were differentially methylated in high-grade prostatic intraepithelial neoplasia and PCa in comparison with benign prostate

tissue samples (false discovery rate-adjusted P-value 1.5). Of the 33 genes, hierarchical clustering analysis demonstrated BNC1, FZD1, RPL39L, SYN2, LMX1B, CXXC5, ZNF783 and CYB5R2 as top

candidate novel genes that are frequently methylated and whose methylation was associated with inactivation of gene expression in PCa cell lines. Pathway analysis of the genes with altered

methylation patterns identified the involvement of a cancer-related network of genes whose activity may be regulated by TP53, MYC, TNF, IL1 and 6, IFN-γ and FOS in prostate pathogenesis.

Our genome-wide methylation profile shows epigenetic dysregulation of important regulatory signals in prostate carcinogenesis.

This work was supported by grant from Department of Defense Program Idea Award; PC101996 to Bernard Kwabi-Addo. This work is also supported by the use of facilities at Howard University

Department of Biochemistry and Molecular Biology, and Children’s National Medical Center.

Children’s National Medical Center, Center for Genetic Medicine Research, Washington, DC, USA

S Wang, J Long, D J Taghipour, P Furbert-Harris & B Kwabi-Addo

Department of Biochemistry and Molecular Biology, Howard University, Washington, DC, USA

Department of Microbiology, Howard University, Washington, DC, USA

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

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