臺灣博碩士論文加值系統

子宮內膜癌在全世界婦科癌症裡是排名第二位，在台灣地區比起其他的婦女癌症，子宮內膜癌的發生率是位居第三位。近年來子宮內膜癌的發病率在近年來有逐漸攀升之趨勢。附基因體修飾(epigenetic modification)的失調，特別是在早期腫瘤的發展，是跟基因突變一樣會推動癌症的發展和增長。
子宮內膜癌的症狀為停經前後陰道之異常出血，向醫生求診之後會先進行子宮擴張刮除術(Dilation And Curettage)做初步的檢查，結果是非典型子宮內膜增生(Atypical hyperplasia)的話,只施行全子宮切除手術(Total Hysterectomy)的治療即可，當全子宮切除手術開下來後,卻發現是子宮內膜癌就必須再動一次腹腔鏡下之淋巴摘除手術(Laparoscopic lymphadenectomy),不僅對病人造成困擾還得支付額外的醫療花費。因此，非典型子宮內膜增生(Atypical hyperplasia)和分化良好的子宮內膜癌兩者的區分，在婦科病理學上是較為困難且重要的鑑別診斷。目前為止並沒有一種標準或常規的檢查是用在子宮內膜癌上。故研究的目的是想利用附基因體修飾(epigenetic modification)的技術去偵測特定基因的DNA甲基化，藉以幫助病理科醫師正確診斷出子宮內膜癌。
所收集的檢體是已經過固定、脫水和包埋的子宮內膜組織蠟塊，實驗分成三組:正常組(Normal)是正常子宮內膜組織20例、癌症組(Cancer)是子宮內膜癌20例以及癌前病變組(Precancer)是子宮內膜不典型增生60例，總共是101個病理蠟塊。從蠟塊中萃取的DNA得先經過亞硫酸氫鈉(Sodium Bisulfite)的處理，再以定量甲基化聚合酶連鎖反應檢測每個基因的甲基化程度。
針對AJAP1, PTGDR, HS3ST2, SOX1基因以Mann-Whitney U test統計出P值各分別為<0.0001，0.0002，0.0004，0.0035，代表在統計學上具非常顯著的意義(P值<0.01)，所代表的意義是指AJAP1, PTGDR, HS3ST2, SOX1這四個基因的DNA甲基化程度用來鑑別正常子宮內膜和子宮內膜癌兩者是可行的。比較子宮內膜癌前期(precancer)和子宮內膜癌(cancer)兩者的結果顯示，AJAP1基因的P值為0.0005，具有非常顯著的意義(P值<0.01)，HS3ST2, SOX1基因的P值分別為0.014，0.023，有顯著性的意義(P值<0.05)，唯獨PTGDR基因的P值是0.22，在統計學上是沒有顯著性意義(P值＞0.05)，代表利用AJAP1, HS3ST2, SOX1三個基因的DNA甲基化程度在鑑別子宮內膜癌前期(precancer)病變和子宮內膜癌(cancer)兩者是可行的。首次發表出AJAP1, HS3ST2, SOX1 三個基因的DNA高度甲基化分析可做為一種具有潛力的生物標記，並偵測出惡性的子宮內膜癌。

Endometrial carcinoma (EC) is the one of the most common cancers in female genital tract worldwide. It can be classified into two major subtypes with respect to histopathology, cell biology and clinical course. Epigenetic aberration is known to be important in human carcinogenesis. Promoter methylation status of SOX1, HS3ST2, AJAP1 and PTGDR, was evaluated in 20 endometrial carcinomas (EC) and normal endometrial tissue by methylation specific PCR. These 4 genes had higher methylation value in patients with EC than in normal controls of AJAP1, PTGDR, HS3ST2, and SOX1 (p < 0.0001, p = 0.0002, p = 0.0004, p = 0.0035, respectively). Atypical hyperplasia (AH) is a premalignant lesion of endometrial pathology. Women with this diagnosis based on endometrial sampling are frequently found to have EC at hysterectomy. The failure of accurately diagnose EC preoperatively in these women can lead to inadequate staging and potentially suboptimal treatment for some women. So, there is a need for other markers to identify women with AH in endometrial sampling harboring an underlying EC. Sixty-one endometrial sampling with pathological diagnosis of AH were analyzed. Fourteen of the sixty-one (23%) AH patients were confirmed to have EC at hysterectomy. Three of 4 genes had higher methylation value in patients with EC hidden in AH compared with AH of AJAP1, HS3ST2 and SOX1 (p = 0.0005, p = 0.014, p = 0.023, respectively). Best cutoff values of the methylation data for different genes were determined to test the sensitivity, specificity, positive predict value (PPV), negative predict value (NPV) and to generate receiver operating characteristic (ROC) curve. ROC curve analysis demonstrated that the sensitivity, specificity, accuracy, PPV and NPV for the best performance for separating EC from AH has a sensitivity of 0.86, 0.71 and 0.71, respectively, and a specificity of 0.72, 0.70 and 0.60, respectively and accuracy of 0.81, 0.72 and 0.70, respectively, and a PPV of 0.48, 0.42 and 0.35, respectively, and a NPV of 0.94, 0.89 and 0.88, respectively. In conclusion, promoter hypermethylation of AJAP1, HS3ST2, PTGDR and SOX1 is found in EC. In addition, we also show for the first time that AJAP1, HS3ST2 and SOX1 hypermethylation analysis may have potential as a EC biomarker for endometrial malignancy.

正文目錄
頁次
中文摘要 09
英文摘要 11
第一章 緒言 13
第一節 子宮內膜介紹 14
第二節 子宮內膜不典型增生與子宮內膜癌診斷的治療 15
第三節 癌症與附基因體調控 19
第四節 SOX1基因 21
第五節 HS3ST2基因 23
第六節 AJAP1基因 25
第七節 PTGDR基因 26
第二章 實驗目的與實驗設計 27
第三章 實驗材料與方法 28
第一節 檢體收集 28
第二節 石蠟切片與常規蘇木素-伊紅染色 29
第三節 去氧核醣核酸(DNA)的萃取與定量 30
第四節 亞硫酸氫鈉處理(Sodium Bisulfite) 34
第五節 定量甲基化聚合酶連鎖反應(Quantitative-MS PCR) 37
第六節 統計分析 40
第四章 實驗結果 41
第一節 比較四個基因SOX1, HS3ST2, AJAP1和PTGDR在正常子宮內膜和子宮內膜癌的甲基化狀態 41
第二節 在子宮內膜癌前期與癌前期開刀後是子宮內膜癌兩者比較SOX1, HS3ST2, AJAP1和PTGDR的甲基化狀態 42
第三節 利用SOX1, HS3ST2, AJAP1和PTGDR檢測子宮內膜癌前期與子宮內膜癌間的敏感度、特異性與預測值比較 46
第四節 合併SOX1, HS3ST2和AJAP1三個基因檢測子宮內膜癌前期與子宮內膜癌間的敏感度、特異性與預測值比較 51
第五章 討論 53
第六章 結論與展望 57
第七章 參考文獻 58

圖目錄

圖一、AJAP1, PTGDR, HS3ST2, SOX1基因在正常子宮內膜和子宮內膜癌的甲基化指數分佈圖 66
圖二、AJAP1, PTGDR, HS3ST2, SOX1基因在子宮內膜不典型增生追蹤後續診斷為正常子宮內
膜、子宮內膜增生、子宮內膜不典型增生及子宮內膜癌的甲基化指數分佈圖 67
圖三、AJAP1, PTGDR, HS3ST2, SOX1基因在子宮內膜不典型增生追蹤後續診斷為癌前期病變
與子宮內膜癌的甲基化指數分佈圖 68
圖四、AJAP1, PTGDR, HS3ST2, SOX1基因鑑別子宮內膜不典型增生和子宮內膜癌的ROC曲線圖 69

表目錄

表一、AJAP1, HS3ST2, SOX1基因的DNA甲基化檢測子宮內膜不典型增生和子宮內膜癌的性能表 70
表二、在子宮內膜不典型增生和子宮內膜癌中利用AJAP1, HS3ST2, SOX1基因單獨及兩個基因合
併DNA甲基化的檢測性能表 71
表三、AJAP1, HS3ST2, SOX1三個基因合併的DNA甲基化檢測子宮內膜不典型增生和子宮內膜癌的性能表 72

附錄目錄

附錄一、在正常子宮內膜、子宮內膜不典型增生和子宮內膜癌上偵測RAR-β，CHFR，E-cadherin，
APC，hMLH1這五個基因的甲基化程度百分比 73
附錄二、在119個子宮內膜癌(第一型和第二型)病例偵測不同的抑癌基因的甲基化程度百分比 74

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