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研究生:詹毓庭
研究生(外文):Yu-Ting Chan
論文名稱:考量DNA甲基化之中介效果對吸煙及肺癌基因表達的影響
論文名稱(外文):Mediation Effect of DNA Methylation between Smoking and Gene Expression in Lung Tissue
指導教授:潘文驥潘文驥引用關係
指導教授(外文):Wen-Chi Pan
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:環境與職業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2018
畢業學年度:107
語文別:中文
論文頁數:62
中文關鍵詞:表基因吸菸DNA甲基化中介變項分析基因表達
外文關鍵詞:EpigeneticsmokingDNA methylationMediationRNA seq
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背景:吸菸已知是肺癌重要的危險因子,而吸菸會透過各種途徑影響肺部基因的表達,其中DNA甲基化為近年受到矚目之表觀基因途徑。目前已有許多研究針對血液組織進行分析,但有研究指出使用肺部組織更能反映吸菸對肺部組織的影響。同時且尚無研究探討DNA甲基化之中介效果,如何解釋抽菸對於肺部組織基因表現的影響。因此我們透過這個研究來釐清DNA甲基化途徑的貢獻性,釐清甲基化作用在眾多表觀基因途徑之中的重要性。
目標:利用因果中介分析(Causal Mediation Analysis),探討吸菸對基因表達的總效果,及透過DNA甲基化中介影響基因表達的間接效果占總效果的中介比例。
方法:研究族群來自美國癌症基因圖譜計畫(The Cancer Genome Atlas, TCGA)於1991-2013年間被診斷罹患肺腺癌(n=306)及肺鱗狀細胞癌(n=310)的患者,吸菸為暴露變項,基因表達為結果變項,DNA甲基化是中介變項。使用多變量線性迴歸模型,並再校正年齡、性別、種族、癌症分期、癌症種類、KRAS及EGFR突變等之可能擾因素,找出同時與吸菸包年數和基因表達顯著相關的DNA甲基化位點,之後再從Gene Expression Omnibus的選出兩個獨立的驗證資料庫 (GSE66836及GSE66863),進行兩階段驗證的方式。經此流程篩選出之基因位點,再透過迴歸分析方法得到總效果及間接效果,並計算DNA甲基化所帶來的中介比例。
結果:重度吸菸族群相較於輕度吸菸的族群,其有較高之吸菸包年數(62.09及21.34),且該族群男性較多、年紀稍長、較多為白人,且有較多人罹患肺鱗狀細胞癌。再經由一連串的分析以及外部驗證之後,我們篩選出在六個DNA甲基化位點,分別坐落在五個不同之基因(PRDM16、CDK6、NETO2、CD109及FAM171B)。其中在PRDM16找到兩個顯著位點(p-value < 0.05),該基因是一個轉錄共同調節的因子,他可以調控褐色脂肪組織中的褐色脂肪細胞的發育。在這6個位點所計算的中介效果比例,其中僅CD109這個基因的位點甲基化有顯著中介影響基因表達,該基因是和訊號傳遞有關的GPI-linked細胞表面抗原。
結論:藉由在本研究所發現的六個DNA甲基化位點,說明DNA甲基化在抽菸對於基因表現的途徑中,扮演重要的角色,但由於其他機制對於基因表達的中介效果仍未釐清,因此未來之研究仍值得關注於此議題,更有助於了解DNA甲基化之重要性。
Smoking will affect gene expression of lung tissue by several pathways. Recently, epigenetic focus on DNA methylation, and use blood to reflect the effect of smoking. Some studies indicated that the lung tissue will be a better choice, because it will direct contact with cigarette smoke. There is no study focusing on mediation effect of DNA methylation between smoking and gene expression. To the best of our knowledge, this is the first study using causal mediation analysis to clarify the mediation proportion of DNA methylation. Our study population is from TCGA (The Cancer Genome Atlas), who diagnosis with lung adenocarcinoma (LUAD) and lung squamous cell cancer (LUSC). We applied multiple linear regression to analyze the association of smoking to DNA methylation and DNA methylation to gene expression, adjusted for age, sex, race, cancer type, cancer stage, KRAS mutation and EGFR mutation. Finally, we externally validated the findings in two other datasets from Gene Expression Omnibus GSE66836 and GSE66863, and further calculated the mediation effect. Totally, six validated CpG sites were validated and they located in on five genes (PRDM16, CDK6, NETO2, CD109 and FAM171B). Over theses six CpG sites, DNA methylation plays an important role between smoking and gene expression, but we still need to clarify other mediation effect of another pathway to know the importance of DNA methylation.
目 錄
中文摘要…………………………………………………………………… i
英文摘要……………………………………………………………………… iii
目錄………………………………………………………………………… iv
圖目錄…………………………………………………………………… vi
表目錄…………………………………………………………………… vii
第一章 前言與研究背景……………………………………… 1
第一節 台灣與全球肺癌及吸菸現況………………………………………………… 1
第二節 DNA甲基化與肺癌基因表達…………………………………………………… 3
第三節 吸菸造成DNA甲基化…………………………………………………… 5
第四節 吸菸影響肺癌基因表達…………………………………………………… 8
第五節 研究動機與目的…………………………………………………… 10
第二章 材料與方法…………………………………………………………… 11
第一節 研究族群及資料庫………………………………………………… 11
第二節 資料標準化流程…………………………………………………… 15
第三節 研究流程概要…………………………………………………… 17
第四節 統計分析…………………………………………………… 18
第三章 分析結果…………………………………………………………… 24
第一節 人口學變項分布-TCGA………………………………………………… 24
第二節 人口學變項分布-GEO…………………………………………………… 24
第三節 在訓練組(TRAIN)中基因位點之甲基化對基因表達的影響…… 25
第四節 在訓練組(TRAIN)中吸菸包年數對基因位點之甲基化影響 25
第五節 兩階段驗證-內部有效性及外部驗證 26
第六節 因果中介分析 27
第四章 討論…………………………………………………………… 29
第一節 主要發現………………………………………………… 29
第二節 與先前文獻的相似及相異處…………………………………………………… 29
第三節 生物機制…… 31
第四節 吸菸引起公共衛生議題與中介變項分析的主要發現 33
第五節 研究長處 35
第六節 研究限制及未來發展 36
第五章 結論…………………………………………………………… 38



參考文獻………………………………………………………… 39
附錄………………………………………………………………………………. 48

圖 目 錄
圖一、分析流程圖………………………………………………… ……48
圖二、TCGA資料處理流程圖……………………………………………… ……49
圖三、本研究因果中介分析模型………………………………………………… 50
圖四、α與β之p值分佈直方圖………………………………………………… 51
圖五、使用delta method計算中介效果顯著性之p值直方圖…………… ……..52
圖六、基因表達量單位轉換分析結果之差異………………………… 53

表 目 錄
表一、TCGA人口學變項分布……………………………………………………54
表二、GEO人口學變項分布………………………………………………………56
表三、alpha與beta之p-value分布情形…………………………………………57
表四、通過驗證(Validated)的 CpG 位點……………………………………..58
表五、因果中介變項分析結果……………………… 59
表六、常應用於中介變項分析方法之結果………………………… 60
表七、基因表達量FPKM及TPM單位轉換後之分析結果差異………………...61
表八、吸菸對基因表達的影響………………………… 62
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