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系統識別號 U0026-1507201118021500
論文名稱(中文) B型肝炎病毒基因序列多樣性及共變異引發肝癌形成之探討
論文名稱(英文) Investigation of HBV Genomic Diversity and Covariance in the Pathogenesis of Hepatocellular Carcinoma
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 99
學期 2
出版年 100
研究生(中文) 顏淑玲
研究生(英文) Shu-Ling Yan
學號 T16984057
學位類別 碩士
語文別 中文
論文頁數 83頁
口試委員 指導教授-張定宗
口試委員-楊孔嘉
口試委員-王憲威
中文關鍵字 B型肝炎病毒  慢性B型肝炎  肝癌  基礎核心蛋白啟動子  共變異分析  基因序列變異性 
英文關鍵字 hepatitis B virus (HBV)  chronic hepatitis B (CHB)  hepatocellular carcinoma (HCC)  basal core promoter (BCP)  covariance network (CN) analysis  genetic diversity 
學科別分類
中文摘要 全球超過三億五千萬人口為慢性B型肝炎感染患者,長期感染B型肝炎病毒(HBV)可能會演變成為肝硬化或肝癌。文獻報導曾指出HBV pre-S基因缺失、pre-C (G1896A)基因突變或基礎核心蛋白啟動子( A1762T/G1764A)雙突變等基因變異可能與肝癌形成有關,然而探討基因體特定區域位點之變異不能完整表達HBV整體基因變異及其共同變異性。本實驗系統性地分析HBV基因序列變異性(含全長基因體及各別基因序列)、胺基酸序列變異性與探討其共變異性等,以深入了解HBV基因變異與肝癌發生之相關性。我們收集93位肝癌患者為實驗組與76位具有正常之ALT數值並無肝硬化之慢性B型肝炎患者做為對照組。分析結果發現肝癌患者中HBV整體基因序列變異性遠大於非肝癌患者,特別是在HBV複製酶、大表面蛋白以及pre-C與核心蛋白等核酸區域。接著,由共變異分析結果中發現肝癌患者比非肝癌患者產生較複雜的共變異對,有趣的是核心蛋白之共變異對只發生在肝癌患者。除此之外,我們更發現肝癌患者基因型C之HBV與基因型B相比產生較多的共變異對,推測與基因型C有較嚴重之疾病和較差的預後有關。最後,我們也發現HBV基因體變異,如pre-S 基因缺失、G1896A基因突變與A1762T/G1764A雙突變較易發生在肝癌患者,特別是基因型C之HBV。總結來看,我們發現HBV不管是基因序列變異性、突變率或胺基酸序列共變異性在肝癌患者中都遠比非肝癌患者高,顯示出特定HBV共變異在肝癌產生的重要性。我們期望可以藉由分析HBV基因體之變異更了解造成肝癌發生的可能原因。
英文摘要 More than 350 million people in the world are chronically infected with hepatitis B virus (HBV). Persistent HBV infection leads to chronic hepatitis B (CHB), which are closely associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). Higher mutation rate of HBV was reported to be a risk of hepatocarcinogenesis. Previous study has demonstrated that specific mutations on various HBV regions, including pre-S deletion, pre-core mutant (G1896A), or basal core promoter (BCP) dual mutant (A1762T/G1764A), were associated with HCC. However, it needs a systematic study to completely investigate the effect of HBV genomes on liver carcinogenesis. To achieve this goal, we analyzed HBV genomic diversity through bioinformatics approach and further performed covariance network (CN) analysis to identify the covariance within viral protein. We collected HBV genomes from sera of 93 HCC patients and 76 CHB controls with normal ALT but no cirrhosis/HCC in this study. HBV genetic diversity, especially in polymerase (p<0.0001), large surface (p<0.0001), and pre-core regions (p<0.0014), was significantly higher in HCC patients than in controls. By CN analysis, more complex pairs in HCC patients were found in all viral proteins. Surprisingly, covariance in core protein was exhibited only in HCC patients but not in controls. In addition, HBV genotype C in HCC patients showed more covariance pairs than genotype B, which may imply more aggressive disease and poor outcome. Meanwhile, we discovered that HBV genomic mutation, including pre-C, BCP dual mutation, or pre-S deletion, were frequently occurred in HCC patients, particularly in those with genotype C HBV. In conclusion, genomic diversity, mutation rate, and covariance of HBV protein were higher in HCC patients than in controls, indicating the significance of certain HBV covariance on the pathogenesis of HCC. We hope to provide a new insight of HBV genomic study on hepatocarcinogenesis.
論文目次 目錄(Index)
中文摘要----------------------------------------------------------------------------I
英文摘要--------------------------------------------------------------------------III
致謝--------------------------------------------------------------------------------V
目錄------------------------------------------------------------------------------VII
表 / 圖 / 附錄 目錄----------------------------------------------------------XI
壹、序論 (Introduction)----------------------------------------------------------1
一、B型肝炎病毒----------------------------------------------------------3
1. B型肝炎病毒的特性---------------------------------------------3
2. B型肝炎病毒的生活史------------------------------------------5
3. B型肝炎病毒的分型---------------------------------------------6
二、慢性B型肝炎-----------------------------------------------------------6
1. B型肝炎的流行病學---------------------------------------------6
2. B型肝炎的自然病程與臨床病徵------------------------------8
3. 慢性B型肝炎的治療---------------------------------------------9
三、肝細胞癌---------------------------------------------------------------10
1. 肝癌的形成原因與臨床病徵 ---------------------------------10
2. 慢性B型肝炎與肝癌之相關性 ------------------------------11
四、B型肝炎病毒基因變異----------------------------------------------12
1. B型肝炎病毒變異種--------------------------------------------12
2. B型肝炎病毒突變點及其與慢性B型肝炎及肝癌生成之相關性------------------13
五、共變異分析------------------------------------------------------------15
1. 共變異之定義與重要性----------------------------------------15
2. 共變異於病毒學研究之應用----------------------------------15
貳、目的與策略 (Aim and strategy)------------------------------------------17
參、材料與方法 (Materials and Methods)-----------------------------------18
一、臨床檢體收集---------------------------------------------------------19
二、血清B型肝炎病毒去氧核糖核酸萃取---------------------------19
三、B型肝炎病毒定量----------------------------------------------------20
四、全長B型肝炎病毒基因選殖---------------------------------------23
1. B型肝炎病毒全長基因體之聚合酶連鎖反應------------23
2.膠體電泳----------------------------------------------------------24
3.膠體核酸物質萃取----------------------------------------------25
4.3’末端加dATP反應--------------------------------------------25
5.聚合酶連鎖反應產物純化-------------------------------------26
6.載體黏合反應----------------------------------------------------27
7.大腸桿菌轉型----------------------------------------------------27
五、含B型肝炎病毒基因之菌落鑑定之聚合酶連鎖反應---------------------------------28
六、菌液培養-------------------------------------------------------------29
七、小量質體萃取------------------------------------------------------30
八、限制酶切割反應----------------------------------------------------31
九、B型肝炎病毒株保存---------------------------------------------32
十、B型肝炎病毒全長基因定序------------------------------------32
十一、B型肝炎病毒基因型分析------------------------------------32
十二、序列整理和分析-------------------------------------------------33
十三、統計學分析-------------------------------------------------------35
肆、結果 (Results) --------------------------------------------------------------36
一、臨床檢體各項數據-------------------------------------------------37
二、HBV核酸序列變異性分析----------------------------------------37
1. HBV全長基因體核酸序列變異性分析--------------------38
2. HBV複製酶核酸序列變異性分析--------------------------38
3. HBV大表面蛋白核酸序列變異性分析--------------------38
4. HBV pre-C與核心蛋白核酸序列變異性分析-------------39
5. HBV X蛋白核酸序列變異性分析--------------------------39
三、HBV胺基酸序列變異性分析-------------------------------------40
1. HBV複製酶胺基酸序列變異性分析-----------------------40
2. HBV大表面蛋白胺基酸序列變異性分析-----------------41
3. HBV pre-C與核心蛋白胺基酸序列變異性分析----------41
4. HBV X蛋白胺基酸序列變異性分析-----------------------42
四、突變位點分析-------------------------------------------------------42
五、共變異分析----------------------------------------------------------46
伍、討論 (Discussion) ----------------------------------------------------------49
一、實驗結果探討-------------------------------------------------------50
二、實驗的困難與挑戰-------------------------------------------------54
三、未來展望及臨床研究上的貢獻----------------------------------55
陸、參考文獻 (References) ---------------------------------------------------56
表/圖/附錄 (Tables, figures, and appendixes)-------------------------------63
作者 (author)--------------------------------------------------------------------83


表/圖/附錄 目錄
圖一、HBV基因體結構與引子設計之示意圖-----------------------------63
圖二、HBV變異種及突變點之發現-----------------------------------------64
圖三、HBV全長基因體放大及利用反轉錄酶基因進行選殖確認-----65
圖四、HBV基因分型-----------------------------------------------------------66
圖五、HBV全長基因體核酸序列變異性分析-----------------------------67
圖六、HBV基因核酸序列變異性分析--------------------------------------68
圖七、HBV胺基酸序列變異性分析-----------------------------------------69
圖八、HBV複製酶共變異性分析--------------------------------------------70
圖九、HBV大表面蛋白共變異性分析--------------------------------------71
圖十、HBV pre-C及核心蛋白共變異性分析-------------------------------72
圖十一、HBV X蛋白共變異性分析-----------------------------------------73
表一、臨床檢體資料分析------------------------------------------------------74
表二、根據基因型分析常見突變位點在肝癌患者與非肝癌患者間
發生的機率-------------------------------------------------------------75
表三、肝癌患者與非肝癌患者HBV基因缺失之分析--------------------76
表四、肝癌及非肝癌患者其HBV各蛋白共變異數量之分析-----------77
表五、本實驗使用引子之序列------------------------------------------------78
附錄一、共變異分析之Observed Minus Expected Squared數學模式--79
附錄二、HBV基因體結構-----------------------------------------------------80
附錄三、HBV生活史-----------------------------------------------------------81
附錄四、慢性B型肝炎自然病程---------------------------------------------82
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