title: Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: association with the BORIS/CTCF expression ratio and advanced stage.
abstract: OBJECTIVE
  Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined.
  
  
  METHODS
  We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer.
  
  
  RESULTS
  CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat-α methylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival.
  
  
  CONCLUSIONS
  DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, SUNY Buffalo, Buffalo, New York 14263, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Woloszynska-Read
authors.forename: Wa
authors.initials: W
authors.lastname: Zhang
authors.forename: Jihnhee
authors.initials: J
authors.lastname: Yu
authors.forename: Petra A
authors.initials: PA
authors.lastname: Link
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.forename: Golda
authors.initials: G
authors.lastname: Collamat
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Akers
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Ostler
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097584:DNA Methyltransferase 3B; D000097642:GADD45 Proteins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C000619697:CTCF protein, human; C456540:CTCFL protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins