title: RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer.
abstract: Treatment of epithelial ovarian cancer consists of surgery plus platinum-taxane based chemotherapy. Neither prognostic nor predictive serum or tissue markers except BRCA1/2 mutations are available thus precluding individualized treatment. Aim of this study is the identification and validation of DNA-methylation markers with prognostic value. Genome-wide array analyses were used to determine methylation patterns in groups of serous EOC with different outcome (PFS < vs. > 3 years, each n = 6) but comparable clinical parameters. Two hundred and twenty differentially methylated regions in tumor tissue of patients with short vs. long PFS (106 hypo- and 114 hypermethylated regions) were identified. Thirty-five of 37 selected CpG islands were validated by MSP using the same samples as for microarray analyses. Six of these regions were analyzed by targeted next-generation bisulfite-sequencing confirming array and MSP results. Validation experiments with an enlarged patient group of Type II EOC samples (PFS <3 years n = 30; >3 years n = 18) revealed the CpG island of RUNX3 as significantly more often methylated in patients with short PFS (10/30 vs. 0/18; p < 0.01). Marker combinations with significantly different methylation frequencies in patient groups reached an increased sensitivity with equal specificity (RUNX3+CAMK2N1; sens 40%; spec 100%; p < 0.01). RUNX3/CAMK2N1 methylation-positive patients of the array-independent subset (n = 36) showed a significantly lower PFS (p < 0.01) but no other difference in clinical parameters compared to methylation-negative patients. Genome-wide methylation analyses reliably identified markers of potentially prognostic value. Hypermethylation of RUNX3/CAMK2N1 is associated with poor clinical outcome in Type II EOC, also after macroscopic complete resection.
authors.affiliation: Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Häfner
authors.affiliation: Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Steinbach
authors.affiliation: Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Diebolder
authors.affiliation: Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dürst
authors.affiliation: Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Runnebaum
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D011506:Proteins / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; C529569:CAMK2N1 protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D011506:Proteins
keywords: DNA methylation; biomarker; epigenetics; epithelial ovarian cancer; prognosis