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Methylome analysis of extreme chemoresponsive patients identifies novel markers of platinum sensitivity in high-grade serous ovarian cancer

Tomar, T., Alkema, N. G., Schreuder, L., Meersma, G. J., Meyer, T., Van Criekinge, W., Klip, H. G., Fiegl, H., Van Nieuwenhuysen, E., Vergote, I., Widschwendter, M., Schuuring, E., van der Zee, A. G. J., de Jong, S. & Wisman, G. B. A. 23-Jun-2017 In : BMC Medicine. 15, 1, p. 116 16 p., 116

Research output: Scientific - peer-reviewArticle

Background: Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients.

Methods: Genome-wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (>= 18 months progression-free survival (PFS), n = 8) and non-responders (

Results: Integrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B, and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation were related with extreme responders and high FAM83A and MYO18B methylation with non-responders. In publicly available advanced stage HGSOC datasets, FZD10 and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS in univariate analysis (hazard ratio (HR) = 0.43; 95% CI, 0.27-0.71; P = 0.001) and multivariate analysis (HR = 0.39; 95% CI, 0.23-0.65; P = 0.003). Consistently, low FZD10 expression was associated with improved PFS (HR = 1.36; 95% CI, 0.99-1.88; P = 0.058). FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays.

Conclusions: By applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies.

Original languageEnglish
Article number116
Pages (from-to)116
Number of pages16
JournalBMC Medicine
Volume15
Issue number1
StatePublished - 23-Jun-2017

    Keywords

  • DNA methylation, Integrated methylome analysis, Ovarian cancer, Platinum-based chemotherapy, Extreme chemoresponders, DNA METHYLATION CHANGES, CPG ISLAND METHYLATION, HUMAN SYNOVIAL SARCOMA, EPIGENETIC REGULATION, EXPRESSION ANALYSIS, SIGNALING PATHWAY, BETA-CATENIN, GENE, BIOMARKERS, FZD10

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