Research Interest

Wnt Pathway

Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

The Wnt pathways control key biological processes that potentially impact on tumour progression and patient survival. We are evaluating DNA methylation at promoter CpG islands (CGIs) of Wnt pathway genes in ovarian tumours at presentation and identify biomarkers of patient progression-free survival.  

Epithelial ovarian tumours prospectively collected through a cohort study, were analysed by differential methylation hybridisation (DMH) at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and progression free survival was examined by Cox proportional hazards model.

DNA methylation is associated with PFS at 20/302 loci (p<0.05, n=111), with 5 loci significant at FDR<10%. 11/20 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 tumour cohort (n=311, adjusted p<0.05).

The data highlights the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identifies methylation at NKD1 and DVL1 as independent predictors of PFS.