https://scholars.lib.ntu.edu.tw/handle/123456789/187990
標題: | 不同胃癌突變表現型的基因變化特徵(1/3) | 作者: | 吳明賢 | 關鍵字: | 胃癌;突變表現型;甲基化表現型;比較基因雜交法;Gastric cancer;mutator phenotype;methylator phenotype;comparative genomic hybridization | 公開日期: | 2000 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 由微衛星體不穩定性(MSI)和微衛星體有關的突變來判定腫瘤的突變表現 型,在癌症的發生扮演重要角色。目前已知有部份的胃癌具有突變表現型,為 了更進一步了解此變化在胃癌的意義,吾人依據10 個微衛星體標記變化的情形 將100 個散發性胃癌患者分成高頻率微衛星體不穩定性(MSI-H)、低頻率微衛星 體不穩定性(MSI-L)和微衛星體穩定性(MSS)三種表型,進一步分析TGF βRII, IGFIIR, BAX, MSH3, MSH6, E2F4, MSH2, MLH1 和p53 等基因突變和 MLH1/MSH2 基因,甲基化及蛋白表現的情形,結果發現27%的胃癌至少有一 個微衛星體不穩定性,其中14%為MSI-H,13%為MSI-L 。比較MSI-H, MSI-L 和MSS 的臨床病理特徵發現MSI-L 和MSS 並無差別,但MSI-H 則有較高頻率 為竇部、腸道型、幽門螺旋桿菌血清陽性和較低比率的淋巴結轉移。在相關基 因變化方面,MSI-H 尚具有較高比率的TGF ρRII, IGFIIR, BAX, MSH3 和E2F4 等基因的移位突變,以及較低比率的p53 突變。此外,14 位MSI-H 中有13 位 有MLH1 基因啟動子的高度甲基化及蛋白質表現減少的情形。吾人初步結論為 MSI-H 胃癌有特殊的表現型及基因變化,其中MLH1 基因的甲基化在此種腫瘤 的癌化過程中扮演重要角色。相對於MSI-H, MSI-L 及MSS 則有不同的臨床病 理特徵和較高頻率的p53 突變,意謂在胃癌發生過程中可能有不同的致病機轉。由於最近在大腸癌發現所謂突變表現型和甲基化表現型(methylator phenotype)有同時發生的情形,因此吾人第二年的重點在於以多種重要基因(p16, E-cadherin, p73, DAPK, GST, MGMT, TIMP-3, THBS1)分析其啟動子上的甲基化 情形,另外並以比較基因雜交法分析不同表現型的基因體變化情形,來進一步 釐清不同胃癌突變表現型的基因變化特徵。 Mutator phenotype judged by microsatellite instability(MSI) and its associated mutations plays an important role in gastric carcinogenesis. A subset of sporadic gastric cancers (GC) exhibits MSI. To define the precise role of MSI in GC, a total of 100 patients with sporadic GC were classified into three groups, i.e., high-frequency MSI (MSI-H), low-frequency MSI (MSI-L) and microsatellite stable (MSS) based on ten microsatellite markers. Mutational analyses of TGFâRII, IGFIIR, BAX, MSH3, MSH6, E2F4, MSH2, MLH1 and TP53 genes, and methylation and protein expression of MLH1 and MSH2 were performed and correlated. Twenty-seven percent of GC showed MSI at least in one locus and could be further graded as MSI-H (14%) and MSI-L (13%). No clinicopathologic difference was noted between GC with MSI-L and MSS. Compared with GC with MSI-L or MSS, GC with MSI-H had a significantly higher frequency of antral location, intestinal subtype, H. pylori seropositivity, but a lower incidence of lymph node metastasis, and displayed a higher frequency of frameshift mutations of TGFâRII, IGFIIR, BAX, MSH3, and E2F4 genes but a lower incidence of TP53 mutations. Furthermore, hypermethylation of MLH1 promoter was responsible for the loss of protein function in 13 of 14 MSI-H tumors. It was concluded that a specific phenotype and a distinct profile of genetic alterations exist in MSI-H GC. We speculate that epigenetic inactivation of MLH1 by methylation plays a crucial role in initiating such a pathway of carcinogenesis. In contrast, GCs with MSS and MSI-L exhibit clinicopathologic features that are distinct from MSI-H tumors and have a higher frequency of TP53 mutations, suggesting that they may evolve through entirely different pathway. Recently, CpG island methylator phenotype with concordant methylation at a number of loci has been reported in a certain portion of colon cancer. To extend our study, we will analyzed methylation status at multiple important genes (p16, E-cadherin, p73, DAPK, GST, MGMT, TIMP-3, THBS1) and compared the global changes using comparative genomic hybridization among different subtypes to further characterize genomic alterations in GC with different mutator phenotypes. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23471 | 其他識別: | 892314B002256 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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