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

Abstract

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 À149) 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. (Cancer Res 2005; 65(19): 8961-7)

Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer

“…A fourth study by Teodoridis et al (2005) failed to detect FANCF methylation in 106 stage III and IV ovarian cancers. It is unclear whether the differences between the studies that are positive for methylation (including the present one) and that of Teodoridis are due to differences in techniques or patient populations.…”

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

“…For instance, clear cell ovarian cancers are reportedly more resistant to chemotherapy than other types (Sugiyama et al, 2000), and this difference in sensitivity may be caused in part by differences in the genes methylated in clear cell and nonclear cell tumours. In fact, Teodoridis et al (2005) reported that methylation of genes involved in DNA repair was significantly associated with response to chemotherapy, while Chan et al (2005) reported that methylation of 18S and 28S ribosomal DNA genes is associated with longer progression-free survival in ovarian cancer. Taken together, these results suggest that differences in the epigenetic signatures between clear cell and other types of ovarian cancer may be a useful diagnostic indicator.…”

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

“…Cells deficient in BRCA1 have reduced efficiency in repairing DNA damage caused by cytotoxic agents. It has been shown that hypermethylation of the BRCA1 promoter region causes increased sensitivity to platinum drugs (Teodoridis et al 2005). Also in two ovarian cancer cell lines decreasing BRCA1 mRNA using inhibition assays correlated to increased sensitivity to platinums (Quinn et al 2007).…”