CDO1基因甲基化做為子宮內膜癌的疾病嚴重度和預後之生物標誌

Abstract

本論文的目的在評估子宮內膜癌患者的CDO1基因啟動子區域甲基化情形，探討在不同組織型態間是否存在甲基化差異，以及是否能夠作為預測子宮內膜癌的疾病嚴重度和預後之指標。 本研究收集了6位良性腫瘤患者(如子宮肌瘤、子宮肌腺症等)的正常子宮內膜(normal endometrium)、4位非典型子宮內膜增生(atypical hyperplasia)的患者以及147位子宮內膜樣細胞癌(endometrioid adenocarcinoma)病人，利用甲基化特異性聚合酶鏈鎖反應、半定量反轉錄聚合酶鏈鎖反應、即時定量聚合酶鏈鎖反應和質量陣列分析組織檢體中CDO1的表現量和啟動子區域的CpG位點甲基化百分比，並加以記錄患者的臨床病理特徵。 另外，我們使用了分數(Score)來評估CDO1基因啟動子區域的10個CpG位點是否與臨床病理參數相關，計分方式為：如果患者的某CpG位點的甲基化百分比高於3/4的其他患者的該CpG位點甲基化百分比則分類為1，如果無高於則分類為0，之後再將患者的每一個CpG位點得到的分數總合。從總和後的分數可以發現，已經停經的病患、FIGO分期後期、肌層侵入大於1/2以及有復發者的分數都較未停經的病患、FIGO分期前期、肌層侵入≦1/2以及無復發者為高。同時我們也進一步分析分數的高低與子宮內膜樣細胞癌病人的存活率是否相關聯，可以發現分數高的病人有顯著較差的無病存活率。 總而言之，子宮內膜樣細胞癌病人的CDO1啟動子區域甲基化程度較正常子宮內膜和非典型子宮內膜增生患者為高，且子宮內膜樣細胞癌病人的臨床特徵若為已經停經、FIGO分期後期、肌層侵入大於1/2以及有發生復發等，其腫瘤組織中的CDO1啟動子區域甲基化程度高，且會有較差的無病存活率和整體存活率。因此，CDO1 可作為子宮內膜樣細胞癌的疾病嚴重度和預後之指標。

The purpose of the study was to evaluate the levels of CDO1 promoter methylation between normal endometrium, atypical hyperplasia, and endometrioid adenocarcinoma. The relationship between the levels of CDO1 promoter methylation and the clinico-pathologic parameters of patients was also discussed. We aimed to investigate whether CDO1 gene methylation takes part in carcinogenesis and can be a biomarker for disease severity and outcome of endometrioid adenocarcinoma. Specimens of endometrial tissues include 6 normal endometrium, 4 atypical hyperplasia and 147 endometrioid adenocarcinoma. The CDO1 expressions and promoter methylation levels were determined by methylation-specific PCR, semi-quantitative RT-PCR, quantitative real-time PCR, and mass array. The clinico-pathologic parameters of these patients were also analyzed. Scoring was used to evaluate the correlations between 10 CpG sites of CDO1 promoter and clinico-pathologic parameters. The sums of score were higher in endometrioid adenocarcinoma tissue than those of normal endometrium. Patients with menopause, advanced stages, depth of myometrial invasion >1/2, or recurrence had significantly higher scores compared to those without menopause, early stages, depth of myometrial invasion ≦1/2, or no recurrence. In addition, by using multi-variate analysis, patients with high scores of CDO1 methylation had significantly shorter progression free survival (PFS). In conclusion, CDO1 can be a potential prognostic biomarker for predicting the outcomes of the patient with endometrioid adenocarcinoma.