2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658614摘要：卵巢癌是最致命的惡性婦科腫瘤，其中漿液性癌是最普遍的卵巢癌。大多數卵巢癌病患都是在晚期才被診斷出來。雖然化學療法已經發展多年且大有進展，大多數病患在化學療法之後仍經常發生腫瘤復發並且死於他們的疾病。因此釐清該類腫瘤的發生機制在卵巢癌裡是很重要的課題。根據細胞核與結構的複雜度，卵巢漿液性腫瘤可以分成漿液性過渡性腫瘤、低惡性度漿液性癌與高惡性度漿液性癌。高惡性度漿液性癌常有TP53的突變，而相對的，低惡性度漿液性癌被認為源於漿液性過渡性腫瘤，則是常有KRAS/BRAF/ERBB2路徑的突變。而從我們最近針對這一類腫瘤進行的全基因檢測來看，低惡性度漿液性癌與高惡性度漿液性癌常有P16INK4a的基因缺損，漿液性過渡性腫瘤則無這一類的變化，而三者都有P14ARF(老鼠是P19ARF這項研究的目標是使用一項新近發展的技術，基因剔除/轉殖鼠，用來建立卵巢漿液性腫瘤的老鼠模型，並釐清該類腫瘤的發生機制。在這項研究過程中，我們計畫同時活化上述常突變的致癌基因與剔除上述常缺損的基因，來觀察並分析腫瘤的生成。 )的基因缺損。目標1︰利用基因剔除/轉殖鼠的技術，我們計畫同時剔除P19ARF目標2︰利用基因剔除/轉殖鼠的技術，我們計畫同時剔除P16基因與活化突變的KRAS/BRAF致癌基因，此兩基因變化常與漿液性過渡性腫瘤有關。INK4a目標3︰利用基因剔除/轉殖鼠的技術，我們計畫同時剔除P16基因與活化突變的KRAS/BRAF致癌基因，此兩基因變化常與低惡性度漿液性癌有關。INK4a此計畫主要是嘗試建立卵巢漿液性腫瘤的老鼠模型，該結果將幫助我們更瞭解該類腫瘤的生成。 基因與活化突變的TP53抑癌基因，此兩基因變化常與高惡性度漿液性癌有關。<br> Abstract: Ovarian cancer is the most lethal malignant gynecologic neoplasm and serous carcinoma represents the most common type of ovarian cancer. Most patients with ovarian carcinomas are diagnosed at advanced stage. Although advances of chemotherapy have developed over the years, most patients eventually develop recurrent carcinomas after chemotherapy and succumb to their disease. Hence clarifying pathogenesis is the one of main issue in ovarian carcinoma.According to nuclear and architectural complexity, ovarian serous tumors can be divided into serous borderline tumor (SBT, carcinoma in situ or intraepithelial carcinoma), low-graded serous carcinoma (LG) and high-graded serous carcinoma (HG). HGs contain frequent TP53 mutations, whereas LGs which were thought as arising from SBTs and harbor mutations in KRAS/BRAF/ERBB2 pathway. From our previous results of genome-wide survey in these tumors, frequent P16INK4a deletion can be found in both HGs and LGs, but not in SBTs. We also found usual deletion of P14ARF(P19ARF in mice) in SBTs and those HGs and LGs with P16INK4aThe objective of this study is to apply a well-developed technology, knockout / transgenic mice, to create mouse models and clarify pathogenesis of ovarian serous tumors. In this study, we propose to knockout the frequently deleted tumor suppressor genes and simultaneously activate the frequent mutant oncogenes and tumor suppressor genes above in mouse models, and observe and analysis possible tumor development. deletion.Specific aim1: Using the technique of knockout/transgenic mice, we plan to knock out P19ARFSpecific aim# 2: Using the technique of knockout / transgenic mice, we plan to knock out P16 and activate the mutatnt oncogene KRAS/BRAF which are related to SBTs simultaneously.INK4aSpecific aim# 3: Using the technique of knockout / transgenic mice, we plan to knock out P16 and activate the mutant oncogene KRAS/BRAF which are related to LGs simultaneously.INK4aThe overall plan tries to build up the animal models of ovarian serous tumors including SBT, LG and HG. Our results may help us to understand more about the tumor genesis of ovarian serous tumors.基因剔除殖鼠基因轉殖鼠漿液性過渡性腫瘤低P16INK4aP14ARFTP53KRASBRAF