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CpG Island Methylation of DNA Damage Response Genes in Advanced Ovarian Cancer

¹ Centre for Oncology and Applied Pharmacology, Cancer Research UK Beatson Laboratories, University of Glasgow; ² Department of Gynaecological Oncology, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom; ³ Department of Medical Oncology, University of Edinburgh, Western Infirmary, Edinburgh, United Kingdom; and ⁴ Department of Medicine, Washington University in St. Louis, St. Louis, Missouri

Requests for reprints: Robert Brown, Department of Medical Oncology, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, G61 1BD Glasgow, Scotland. Phone: 011-141-330-4335; Fax: 011-141-330-4127; E-mail: r.brown{at}beatson.gla.ac.uk.

We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, <10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position –149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation.

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