title: DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity.
abstract: Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined the nature, extent, and timing of DNA hypomethylation changes in human prostate cancer. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in (5me)C content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease. Furthermore, we found that, whereas some LINE1 promoter hypomethylation does occur in primary prostate cancers compared with normal tissues, this LINE1 hypomethylation is significantly more pronounced in metastatic prostate cancer. Next, we carried out a tiered gene expression microarray and bisulfite genomic sequencing-based approach to identify genes that are silenced by CpG island methylation in normal prostate cells but become overexpressed in prostate cancer cells as a result of CpG island hypomethylation. Through this analysis, we show that a class of cancer testis antigen genes undergoes CpG island hypomethylation and overexpression in primary prostate cancers, but more so in metastatic prostate cancers. Finally, we show that DNA hypomethylation patterns are quite heterogeneous across different metastatic sites within the same patients. These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. syegnasu@jhmi.edu
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.forename: Michael C
authors.initials: MC
authors.lastname: Haffner
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bora
authors.initials: B
authors.lastname: Gurel
authors.forename: Toby C
authors.initials: TC
authors.lastname: Cornish
authors.forename: Zhijin
authors.initials: Z
authors.lastname: Wu
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Irizarry
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Theodore L
authors.initials: TL
authors.lastname: DeWeese
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: G Steven
authors.initials: GS
authors.lastname: Bova
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.forename: William G
authors.initials: WG
authors.lastname: Nelson
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D007150:Immunohistochemistry; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D053719:Tandem Mass Spectrometry