title: Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival.
abstract: OBJECTIVE
  Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS).
  
  
  METHODS
  Epithelial ovarian tumors (screening study n = 120, validation study n = 61), prospectively collected through a cohort study, were analyzed by differential methylation hybridization at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and PFS was examined by Cox proportional hazards model.
  
  
  RESULTS
  DNA methylation is associated with PFS at 20 of 302 loci (P < 0.05, n = 111), with 5 loci significant at false discovery rate (FDR) less than 10%. A total of 11 of 20 loci retain significance in an independent validation cohort (n = 48, P ≤ 0.05, FDR ≤ 10%), and 7 of these loci, at FZD4, DVL1, NFATC3, ROCK1, LRP5, AXIN1, and NKD1 genes, are independent from clinical parameters (adjusted P < 0.05). Increased methylation at these loci associates with increased hazard of disease progression. A multivariate Cox model incorporates only NKD1 and DVL1, identifying two groups differing in PFS [HR = 2.09; 95% CI (1.39-3.15); permutation test P < 0.005]. Methylation at DVL1 and NFATC3 show significant association with response. Consistent with their epigenetic regulation, reduced expression of FZD4, DVL1, and ROCK1 is an indicator of early-disease relapse in an independent ovarian tumor cohort (n = 311, adjusted P < 0.05).
  
  
  CONCLUSIONS
  The data highlight the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identify methylation at NKD1 and DVL1 as independent predictors of PFS.
authors: Epigenetics Unit; Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom.
authors: Wei
authors: W
authors: Dai
authors: Jens M
authors: JM
authors: Teodoridis
authors: Constanze
authors: C
authors: Zeller
authors: Janet
authors: J
authors: Graham
authors: Jenny
authors: J
authors: Hersey
authors: James M
authors: JM
authors: Flanagan
authors: Euan
authors: E
authors: Stronach
authors: David W
authors: DW
authors: Millan
authors: Nadeem
authors: N
authors: Siddiqui
authors: Jim
authors: J
authors: Paul
authors: Robert
authors: R
authors: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D000077216:Carcinoma, Ovarian Epithelial; D002352:Carrier Proteins / Q000378:metabolism; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C449091:NKD1 protein, human; D051153:Wnt Proteins