Fiegl Heidi, Windbichler Gudrun, Mueller-Holzner Elisabeth, Goebel Georg, Lechner Matthias, Jacobs Ian J, Widschwendter Martin
Department of Gynecological Oncology, UCL EGA Institute for Women's Health, University College London, United Kingdom.
Int J Cancer. 2008 Aug 1;123(3):725-9. doi: 10.1002/ijc.23563.
Epigenetic alterations play a major role in cancer. Recently we reported that stem cell Polycomb group targets (PcGTs) are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than nontargets. To identify potential, prognostic DNA methylation markers in ovarian cancer we analyzed the DNA methylation at 71 different loci in 22 ovarian cancers and 18 non-neoplastic ovarian specimens by means of a quantitative, real-time PCR-based technique (MethyLight). We identified DNA methylation of HOXA10 and HOXA11, both of them PcGTs, to be the best discriminators between cancer and non-neoplastic tissue. In an independent set consisting of 92 ovarian cancer specimens further analysis demonstrated that HOXA11 DNA methylation is (i) strongly associated with the residual tumor after cytoreductive surgery and (ii) is a marker indicating poor prognosis. HOXA11 DNA methylation was independently associated with poor outcome [relative risk for death 3.4 (95% CI 1.2-9.9; p = 0.03)]. These findings support the view that the technical inability to optimally cytoreduce ovarian cancer is associated with particular molecular alterations in the tumor which per se define a subgroup of patients with poor outcome.
表观遗传改变在癌症中起主要作用。最近我们报道，干细胞多梳蛋白家族靶点（PcGTs）发生癌症特异性启动子DNA高甲基化的可能性比非靶点高12倍。为了鉴定卵巢癌潜在的预后DNA甲基化标志物，我们采用基于定量实时PCR的技术（MethyLight）分析了22例卵巢癌和18例非肿瘤性卵巢标本中71个不同位点的DNA甲基化情况。我们发现HOXA10和HOXA11（二者均为PcGTs）的DNA甲基化是区分癌症组织和非肿瘤组织的最佳指标。在一个由92例卵巢癌标本组成的独立队列中，进一步分析表明，HOXA11 DNA甲基化（i）与肿瘤细胞减灭术后的残留肿瘤密切相关，（ii）是一个提示预后不良的标志物。HOXA11 DNA甲基化与不良预后独立相关[死亡相对风险为3.4（95%CI 1.2 - 9.9；p = 0.03）]。这些发现支持了这样一种观点，即卵巢癌无法实现最佳肿瘤细胞减灭的技术原因与肿瘤中特定的分子改变有关，而这些分子改变本身就定义了一组预后不良的患者亚群。
