Department of Gynaecological Oncology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
Endocr Relat Cancer. 2010 Jun 25;17(3):663-73. doi: 10.1677/ERC-10-0014. Print 2010 Sep.
Promoter methylation is a gene- and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.
启动子甲基化是一种基因和癌症类型特异性的表观遗传事件，在肿瘤发展中起着重要作用。由于子宫内膜样（子宫内膜样腺癌，EEC）和浆液性子宫内膜癌（子宫乳头状浆液性癌，UPSC）表现出不同的临床、组织学和分子遗传学特征，我们假设这些差异可能反映在表观遗传现象中。鉴定一组甲基化生物标志物可能有助于正确组织学分类这两种亚型，仅基于形态学并不总是容易的。采用甲基化特异性多重连接依赖性探针扩增来评估不同肿瘤抑制基因在 EEC 和 UPSC 中的启动子甲基化程度。甲基化结果与组织学和生存相关。所有基因的中位累积甲基化指数在 EEC（124）中明显高于 UPSC（93）（P<0.001）。EEC 中 CDH13 和 MLH1 的启动子甲基化更为常见，而 UPSC 中 CDKN2B 和 TP73 的甲基化更为常见。EEC 中几乎 90%和 UPSC 中 70%可以通过 CDH13 和 TP73 预测。在 EEC 中，MLH1 的甲基化与无病生存期（DFS；P<0.0001）和总生存期（OS；P=0.005）较短相关。在多变量模型中，MLH1 甲基化是 DFS（P=0.002）的另一个预后因素。总之，EEC 中启动子甲基化比 UPSC 更为常见。一组甲基化生物标志物可用于区分子宫内膜癌的两种组织学亚型。此外，MLH1 的甲基化可能在 EEC 中具有预后价值。
