title: Identification of novel DNA-methylated genes that correlate with human prostate cancer and high-grade prostatic intraepithelial neoplasia.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 <0.05; β-value 0.2; fold change >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.
  
  
  CONCLUSIONS
  Our genome-wide methylation profile shows epigenetic dysregulation of important regulatory signals in prostate carcinogenesis.
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research, Washington, DC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Devaney
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Funda
authors.forename: J
authors.initials: J
authors.lastname: Long
authors.forename: D J
authors.initials: DJ
authors.lastname: Taghipour
authors.forename: R
authors.initials: R
authors.lastname: Tbaishat
authors.forename: P
authors.initials: P
authors.lastname: Furbert-Harris
authors.forename: M
authors.initials: M
authors.lastname: Ittmann
authors.forename: B
authors.initials: B
authors.lastname: Kwabi-Addo
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D018450:Disease Progression; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
chemical_list: D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine