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標題: | DNA 甲基化和早發肝細胞癌之關聯性:手足配對之病例對照研究 Relationship between DNA Methylation and Early-Onset Hepatocellular Carcinoma: Case-Sibling Matched Study |
作者: | Wen-Jie Liu 劉彣潔 |
指導教授: | 于明暉(Ming-Whei Yu) |
關鍵字: | 早發肝細胞癌,DNA 甲基化,白血球, early-onset HCC,DNA methylation,leukocytes, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 研究背景:肝細胞癌大部分是由慢性HBV感染所導致。目前早發肝細胞癌的病因不明瞭且缺乏適當的生物標記,DNA甲基化會受到基因、環境和臨床前期疾病的影響,因此DNA甲基化或許能解釋手足間罹患早發肝細胞癌風險的差異,但目前DNA甲基化和早發肝細胞癌的關係仍未知。本研究使用手足配對樣本去探討血液DNA甲基化和HBV導致的早發性肝癌之間的相關性。 材料與方法:本研究使用手足配對病例對照研究,包括134位早發性肝細胞癌患者和174位他們的未罹病手足做為對照個案,早發肝細胞癌的定義為發病年齡50歲或以下。我們採用兩階段的研究設計,第一階段由小樣本(包括48個病例和59個對照)篩選九個標記,顯著或重要的五個標記再進行擴大分析,我們使用的DNA是由白血球中所萃取,透過焦磷酸定序來量化甲基化的程度。 結果:在校正干擾因子包括年齡和BCP雙突變後,我們發現在3個探針標的的序列上,有9個CpG位點的DNA甲基化和肝細胞癌呈現顯著的負相關,以最顯著的CpG位點而言,隨甲基化四分位數下降,肝細胞癌的相對危險性指標(95%信賴區間)各為1.00、4.23(1.27-14.15)、13.73(3.43-54.99)和47.68(10.49-216.74)。我們也發現五個和肝細胞癌有關的CpG位點和HBV基因型、病毒量或BCP雙突變有關,此外,兩個和肝細胞癌有關的CpG位點也分別和血清α-胎兒蛋白濃度及腫瘤大小有關。 結論:白血球上的甲基化標記可能和早發性肝細胞癌罹病或預後有關,而且這些甲基化標記可能參與HBV導致肝細胞癌的過程,這些標記或許能用作肝細胞癌的罹病風險預測或預後指標,但未來仍需要前瞻性研究來證明這些標記的可用性。 Introduction: Hepatocellular carcinoma (HCC) is mostly attributed to chronic HBV infection. However, cause of early-onset HCC is unclear and there is not an appropriate biomarker to detect early-onset HCC at present. DNA methylation is a dynamic change affected by genetics, environments and preclinical diseases. Therefore, DNA methylation may interpret the difference in risk of early-onset HCC between siblings, but the correlation between DNA methylation and early-onset HCC is unknown. In this study, we use case-sibling matched study to determine whether DNA methylation in leukocytes is associated with early-onset HCC in relation to HBV. Materials and Methods: We used case-sibling matched study involving a total of 134 early-onset HCC cases (ages of diagnosis with HCC were less than or equal to 50 years of age) and 174 their unaffected siblings. We used two-stage study design to select candidate methylation markers. 48 matched sets (including 48 cases and 59 sibling controls) were used for screening nine candidate methylation markers, and five significant or important markers were then tested for remaining study subjects. DNA was extracted from buffy coat, and methylation levels were quantified by using pyrosequencing. Results: Methylation on three probes targeting sequences included 9 CpG sites were significantly inversely related to HCC after adjusting for age and BCP double mutation. In most significant CpG site, odds ratios (95% CI) of HCC were increased with decreasing quartiles of methylation levels, which were 1.00, 4.23 (1.27-14.15), 13.73 (3.43-54.99), and 47.68 (10.49-216.74). We also found that five HCC-related CpG sites were associated with HBV genotype, viral load or BCP double mutation. In addition, two HCC-related CpG sites were associated with serum α-fetoprotein levels and HCC tumor size, respectively. Conclusions: We confirmed that methylation markers measured on leukocytes were associated with early-onset HCC or prognosis of HCC, and these markers may contribute to risk of HCC by coordinating with HBV. In addition, these markers also have potential to use as HCC risk assessment or prognostic biomarkers of HCC. However, prospective studies are still needed in the future to determine the availability of these markers. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53076 |
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顯示於系所單位: | 流行病學與預防醫學研究所 |
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