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RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer
Norman Häfner1, Daniel Steinbach1, Lars Jansen1
1Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
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.
Insights
New DNA methylation markers, RUNX3 and CAMK2N1, show prognostic value in epithelial ovarian cancer (EOC). Hypermethylation is linked to shorter progression-free survival (PFS) in Type II EOC patients, enabling potential for individualized treatment strategies.
Area of Science:
- Oncology
- Epigenetics
- Molecular Diagnostics
Background:
- Epithelial ovarian cancer (EOC) treatment relies on surgery and chemotherapy, lacking prognostic/predictive markers beyond BRCA1/2 mutations.
- Individualized treatment for EOC is currently limited due to the absence of reliable biomarkers.
- Identifying novel markers is crucial for improving patient outcomes and treatment strategies in EOC.
Purpose of the Study:
- To identify and validate DNA methylation markers with prognostic significance in epithelial ovarian cancer.
- To explore the potential of DNA methylation patterns for predicting patient outcomes, specifically progression-free survival (PFS).
- To investigate the association of specific methylation markers with clinical parameters in Type II EOC.
Main Methods:
- Genome-wide array analysis was employed to compare methylation patterns in EOC tissues from patients with short (<3 years) versus long (>3 years) PFS.
- Differentially methylated regions were identified, followed by validation using methylation-specific PCR (MSP) and targeted next-generation bisulfite sequencing.
- Validation experiments utilized an enlarged patient cohort of Type II EOC samples to confirm the prognostic value of identified markers.
Main Results:
- Two hundred and twenty differentially methylated regions were identified, with 35 selected CpG islands validated.
- Hypermethylation of the RUNX3 CpG island was significantly more frequent in patients with short PFS (p<0.01).
- Marker combinations, such as RUNX3 and CAMK2N1, demonstrated increased sensitivity (40%) and specificity (100%) for predicting poor outcome. RUNX3/CAMK2N1 methylation-positive patients showed significantly lower PFS (p<0.01).
Conclusions:
- Genome-wide methylation analysis successfully identified markers with potential prognostic value in EOC.
- Hypermethylation of RUNX3 and CAMK2N1 is significantly associated with poor clinical outcome and shorter PFS in Type II EOC patients, even after complete resection.
- These findings suggest that RUNX3/CAMK2N1 methylation could serve as a valuable biomarker for individualized treatment strategies in EOC.
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