Imaging, Diagnosis, Prognosis Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival
نویسندگان
چکیده
Purpose: 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). Experimental Design: Epithelial ovarian tumors (screening study n 1⁄4 120, validation study n 1⁄4 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 1⁄4 111), 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 1⁄4 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 onlyNKD1 andDVL1, identifying two groups differing in PFS [HR1⁄4 2.09; 95%CI (1.39–3.15); permutation test P < 0.005]. Methylation atDVL1 andNFATC3 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 1⁄4 311, adjusted P < 0.05). Conclusion: 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. Clin Cancer Res; 17(12); 4052–62. 2011 AACR.
منابع مشابه
Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival.
PURPOSE 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). EXPERIMENTAL DESIGN Epithelial ovarian tumors (screening study n = 120, validation s...
متن کاملTwo Steps Methylation Specific PCR for Assessment of APC Promoter Methylation in Gastric Adenocarcinoma
Gastric Cancer (GC) is the second most common cancer in the world and a leading cause of cancer-related mortality. Methylation of promoter CpG islands (CGIs) belonging to tumor suppressor genes causes transcriptional silencing of their corresponding genes leading to carcinogenesis and other disorders. Adenomatous Polyposis Coli (APC) a tumor suppressor gene is inactivated by methylation of prom...
متن کاملDysregulation of the WNT Signaling Pathway Through Methylation of Wnt Inhibitory Factor 1 and Dickkopf-1 Genes among AML Patients at the Time of Diagnosis
Background: In acute myeloblastic leukemia, a large number of tumor suppressor genes are silenced through DNA methylation such as CDKN2B & p73. Wnt inhibitory factor 1 (WIF1) and Dickkopf-3 (DKK-1) are negative regulators of Wnt signaling pathway. In the present study, we evaluated the methylation status of WIF1 and DKK-1 genes in acute myeloblastic leukemia patients. Patients and Methods: ...
متن کاملMethylation microarray analysis of late-stage ovarian carcinomas distinguishes progression-free survival in patients and identifies candidate epigenetic markers.
PURPOSE The purpose of this study was to profile methylation alterations of CpG islands in ovarian tumors and to identify candidate markers for diagnosis and prognosis of the disease. EXPERIMENTAL DESIGN A global analysis of DNA methylation using a novel microarray approach called differential methylation hybridization was performed on 19 patients with stage III and IV ovarian carcinomas. R...
متن کاملPredicting CpG Islands and DNA Methlation in the Cow Genome Using DNA Microarray Meta-Analysis and Genome Wide Scanning
DNA methylation is a type of epigenetic changes that directly affects DNA. In mammals, DNA methylation is essential for fetal development and stem cell differentiation and this phenomenon essentially occurs within the CpG islands. In this study, two methods were used to study the DNA methylation profile of cow genome. In the first method, the DNA methylation profile of the differentially expres...
متن کامل