2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658615摘要：子宮內膜癌在美國是最常見的婦科惡性腫瘤，在整個女性癌症發生率中排名第四。在台灣，子宮內膜癌也趆來趆重要。目前，女性癌症發生率中排名第八，而在女性生殖系統中，僅次於子宮頸癌，排名第二。子宮內膜癌中，百分之八十至八十五，屬於第一型的類子宮內膜型癌。這類腫瘤的發生通常是與過度的動情激素刺激而無黃体激素保護有關，且通常先經過一個組織學上可辦認的癌前驅病灶。雖然已有各種與這類癌症相關的基因變化被發現，比如 PTEN腫瘤抑制基因，KRAS致癌基因，β-catenin (CTNNB1)基因子及微衛星不穩定現象等。但為了要進一步了解子宮內膜類子宮內膜型癌的致病機轉，找出更多相關的腫瘤生成與癌化的基因是不可避免的。此外，在百分之十五至二十的子宮內膜癌屬於第二型，這一類子宮內膜癌的發生通常是與女性賀爾蒙刺激無關，臨床上主要發生在較為年長的病人，通常沒有組織學上可辦認的癌前驅病灶，P53腫瘤抑制基因的突變目前被認為是早期癌生成的主要基因變化。常見的組織形態分化較差，主要包括乳突狀漿液型癌、透明細胞型癌、或混合型癌等。第二型子宮內膜癌的預後遠較第一型差，且目前對第二型子宮內膜癌的瞭解，因為病例數目較少的緣故，遠不及第一型的類子宮內膜型癌。因此找出更多與第二型子宮內膜癌相關的腫瘤生成與癌化的基因是非常迫切的。此一研究計劃的目標是使用一項新近發展的技術，單核酸多型性陣列，用來鑑定第一型與第二型子宮內膜癌的有關腫瘤生成與惡化的基因複製數的變化。 在這項研究過程中，我們使用SNP 陣列來確定至少三十例第一型子宮內膜癌(十五例高惡性度與十五例低惡性度)及至少十例第二型子宮內膜癌基因組的DNA複製數的變化。目標一︰對子宮內膜類子宮內膜型癌(第一型)執行單核酸多型性陣列分析，找到最常見的基因組變化，並針對高惡性度與低惡性度子宮內膜類子宮內膜型癌，把它們的基因組變化做比較。目標二︰將對第二型子宮內膜癌執行單核酸多型性陣列分析的結果，與第一型子宮內膜癌多型性陣列分析結果相比較，以進一步釐清二者間的關係。我們從單核酸多型性陣列分析獲得的結果將把腫瘤生成與癌化的基因的分子病原學弄得更清楚並且可能為預後的評估和藥物治療提供一個新的遺傳學的標記。<br> Abstract: Endometrial cancer is the most frequent gynecologic malignancy and the fourth most frequently diagnosed cancer in the United States. In Taiwan, endometrial carcinoma is more and more important. Currently, it is the 8th most common cancer in women and the second most common cancer in female genital system.Approximately 80-85% of newly diagnosed cases of endometrial cancer are of endometrioid histology (so-called Type 1), and these have been associated with unopposed estrogen exposure, and are often antedated by premalignant lesions. Although a wide variety of cancer-related genetic alterations have been analyzed in this tumor type, such as PTEN tumor suppressor gene, microsatellite instability (MSI), KRAS oncogene, and β-catenin (CTNNB1) gene, for further clarifying the pathogenesis of endometrial endometrioid adenocarcinoma, identification of the more genes related to tumor genesis and progression is inevitable.In addition, the remaining 15-20% endometrial cancers belong to Type 2 endometrial carcinomas. The tumors of this group are more commonly seen in elder patients (seventh and eighth decades) but do not arise in association with hyperestrogenism, obesity or diabetes. No evident antedated premalignant lesions can be found as a prevention target. Mutations of tumor suppressor gene p53 were thought as early major genetic event. In this group, tumors are generally more poor-differentiated and include uterine papillary serous carcinoma (UPSC), endometrial clear cell adenocarcinoma or mixed type. These tumors overall have a poorer prognosis than endometrioid tumors, and the factors predisposing to their development are less well defined due to much smaller tumor populations. For further clarifying the pathogenesis of Type 2 endometrial carcinomas, identification of the more genes related to tumor genesis and progression is also necessary.The objective of this study is to apply a newly and well-developed technology, SNP (single nucleotide polymorphism) array, to identify copy number variations which may be related to tumor genesis and progression in Type 1 and Type 2 endometrial carcinomas. In this study, we propose to apply SNP array to assess genomic landscape of DNA copy number changes in at least 30 Type 1 (endometrioid adenocarcinoma 15 high grade 15 low grade) and at least 10 Type 2 endometrial carcinomas.Aim 1: Perform SNP array in endometrial endometrioid adenocarcinoma (Type 1) and then find out the most frequent genetic copy number change and compare their genomic profiles between high grade and low grade lesions.Aim 2: Perform SNP array in Type 2 endometrial carcinomas and compare these results to the results of Aim 1, to clarify the relationship and difference between Type 1 and Type 2 endometrial carcinomas..Our results obtained from SNP array analysis will shed a new light on the molecular etiology of tumor genesis and progression and will highly likely provide a new set of genetic markers for outcome prediction and novel targets for drug intervention to treat endometrial cancer.