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研究生:宋姿頤
研究生(外文):Tzu-I Sung
論文名稱:砷暴露與肝癌之劑量效應關係及生物指標應用之評估
論文名稱(外文):Evaluation of Dose-response Relationship between Arsenic and Liver Cancer and Application of Biomarker
指導教授:郭浩然郭浩然引用關係
指導教授(外文):How-Ran Guo
學位類別:碩士
校院名稱:國立成功大學
系所名稱:環境醫學研究所
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:2002
畢業學年度:90
語文別:中文
論文頁數:66
中文關鍵詞:肝癌死亡率生物性指標上皮生長因子受體
外文關鍵詞:epidermal growth factor receptorarsenicliver cancerbiomarkermortality
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全台灣有五十萬以上的居民曾經飲用含砷量超過0.05ppm的水,因此砷的健康效應乃是公共衛生的重要課題。過去的一世紀來,已有許多研究證實飲水含砷及癌症之間的關係。早在1950年代就有研究學者報告食入砷所引起的肝癌,但目前對於其劑量效應關係的數據卻很少,而且沒有較具特異性的生物指標。本研究目的在於使用地理環境資料評估飲水含砷引起肝癌的劑量效應關係,同時評估以上皮因子生長因子受體當作砷引起肝癌的生物指標之可行性,以期應用於可能罹患癌症的易感群和高危險族群,早期診斷、早期治療。
在井水中砷含量方面,本研究採用一井水普查之測量報告,其中包括烏腳病流行區與非烏腳病流行區計138個村里。依據此調查結果將水中砷濃度分成6組,分別為低於0.05 mg/L、0.05~0.08 mg/L, 0.09∼0.16 mg/L、0.17∼0.32 mg/L、0.33∼0.64 mg/L,以及高於0.64 mg/L。肝癌死亡資料是來自於各鄉鎮戶政事務所,收集的時間從1971年1月1日至1990年12月31日,使用多變項回歸模式分析飲水中砷濃度及肝癌死亡率之相關性。之後,再對砷濃度做事後檢定之分層分析(post-hoc analysis),將所有村里砷濃度分為三組,分別是低於0.05 mg/L、0.05~0.64 mg/L及高於0.64 mg/L。此外,我們以成大醫院及嘉義基督教醫院住院之肝癌病患成立一個研究族群,同時找無任何一種癌症的住院病人或健檢民眾做對照組,針對性別、年齡,以及B、C型肝炎等可能的干擾因子進行配對,評估其血清上皮生長因子受體表現與肝癌之關係。血清中上皮生長因子受體是以酵素結合免疫吸附分析法測量。所有數據分析是使用SAS統計軟體檢定。
在歷時20年研究期間,可觀察到138村因肝癌死亡的男性有802位,女性則為301位。在調整年齡並以最低濃度組作為對照之後,發現濃度最高組其肝癌死亡率有明顯的上升,不論男性或是女性皆達統計學上顯著意義,但在於其他砷濃度組別則無此相關。
研究分析200個血清樣本,包括100個肝癌患者及100個對照。所測得上皮生長因子受體的平均濃度,病例組與對照組濃度以t test作檢定後發現達統計上顯著差異(624.7 ± 136.5 fmol/mL比238.9 ± 21.2 fmol/mL,p=0.007)。經配對可能的干擾因子(性別、年齡、肝炎狀態)之50個肝癌病人與50個對照組,其血清中上皮生長因子受體的平均濃度達統計學上顯著差異(p=0.0001)。針對烏腳病地區與非烏腳病地區肝癌病人血清中上皮生長因子受體總計各30組,烏腳病地區的平均濃度637.6 ± 221.5 fmol/mL明顯高於非烏腳病地區371.8 ± 29.1 fmol/mL,結果達統計學上顯著差異(p=0.0001)。
研究結果顯示高濃度砷對於人類是很可能具致肝癌性,上皮生長因子受體在肝癌上會過度表現。未來則希望進一步辨識出上皮生長因子受體在與砷相關肝癌致病機轉中所扮演的角色,以期能實際應用於烏腳病地區高危險族群尋求早期診斷、早期治療。
More than half a million residents in Taiwan had drunk water with arsenic levels higher than 0.05 ppm. Therefore, health effects of arsenic constitute an important public health problem. The association between arsenic ingestion and cancer has been documented for more than a century. Liver cancers were observed among patients of arsenic intoxication since the 1950s, but data on the dose-response relationship were quite limited, and no specific biomarker is currently available. The objective of this study is to evaluate the dose-response relationship using data from a large study area and the feasibility of using epidermal growth factor receptor protein(EGFR)as a biomarker to identify susceptible and high-risk individuals of liver cancer for possible early intervention.
Original measurement reports on arsenic levels in the drinking water from a census survey of wells conducted by the government were available for 138 villages included in this study. According to the method applied in the survey, arsenic levels were categorized into six categories: below 0.05 mg/L, 0.05∼0.08 mg/L, 0.09∼0.16 mg/L, 0.17∼0.32 mg/L, 0.33∼0.64 mg/L, and above 0.64 mg/L. Death certificates gathered by the township household registry offices between January 1, 1971 and December 31, 1990 were reviewed to identify cases of liver cancer. Multi-variate regression models were applied to assess correlations between arsenic levels in drinking water and mortality of liver cancer. In addition, we have established a study cohort of patients of liver cancer at the National Cheng Kung University Hospital and the Chia-Yi Christian Hospital, and selected hospital-based controls. EGFR levels in sera were determined by enzyme-linked immunosorbent assay (ELISA). SAS was used to conduct statistical analyses.
During the 20-year period, 802 male and 301 female mortality cases of liver cancer were identified. After adjusting for age, in comparison with the reference group (below 0.05 mg/L), arsenic levels above 0.64 mg/L were associated with a significant increase in the mortality of liver cancer in both genders. No significant effect was observed for other arsenic categories.
We analyzed 200 serum samples (100 cases and 100 controls), and found a significant difference in the EGFR levels between the study and the control groups (624.7 ± 136.5 fmol/mL vs. 238.9 ± 21.2 fmol/mL,p=0.007). After matching potential confounders, including sex, age, and hepatitis B and C, the result indicated there was significant difference between 50 cases and 50 controls (p=0.0001). We also compared EGFR concentration of liver patients among residents in blackfoot disease (BFD) area with those in non-BFD area. After analyzing 30 BFD case and 30 non-BFD control samples, we found significant difference between two means (637.6 ± 221.5 fmol/mL v.s. 371.8 ± 29.1 fmol/mL,p=0.0001).
The results suggested a carcinogenic effect of high arsenic levels in drinking water on liver, and we found EGFR was over-expressed in patients of liver cancer. Further studies are needed to clarify the role of EGFR biomarker in the carcinogenic mechanism of liver cancer. Furthermore, we hope to identify the high-risk population for possible early intervention.
中文摘要…..………………………………………………………...Ⅰ
英文摘要………………………………..……….………………….Ⅲ
致謝…………………………………………..…...………………..Ⅵ
目錄……………………………………….…...……...……………..Ⅷ
圖目錄………………………….………….……..………..…………Ⅸ
表目錄…………………………..………………...………….………Ⅹ
第一章 緒論………………...…………………….….………………1
1-1 前言…....…………………………...……………………..1
1-2 研究目的…………………………….……….……………2
第二章 文獻回顧……………………….…………………..………3
2-1 砷之物理及化學性質…………..………….…………..3
2-2 砷中毒之可能性..…..………………..………………..4
2-3 砷暴露之致癌效應……………………………………..6
2-4 飲水含砷與肝癌之劑量效應關係研究……………11
2-5 砷暴露之肝癌細胞學型態………………………….…13
2-6 肝血管肉瘤……….………………………………..…15
2-7 上皮生長因子受體……………………………………18
第三章 材料與方法………………………………………………21
3-1 研究材料………………………………………………21
3-1-1 研究類型………………………………………….21
3-1-2 砷暴露與肝癌之劑量效應關係…………………21
3-1-3 肝癌生物性指標之評估………...……………….22
3-2 研究方法…………………………………………………24
3-2-1 肝癌死亡率………………………………………24
3-2-2 多變項線性回歸模式…………………………..24
3-2-3 事後分析…………………………………..……….25
3-2-4 酵素結合免疫吸附分析法……………….………26
3-2-5 統計應用軟體……………………………………27
第四章 研究結果…………………………………………………...28
4-1 砷濃度和肝癌死亡率之劑量效應關係結果…….28
4-2 砷濃度和肝癌死亡率之分層檢定分析…………30
4-3 肝癌患者與健康族群血清中上皮生長因子受體.31
4-4 烏腳病地區與非烏腳病地區肝癌患者血清中上皮生長因子受體之比較…………..….………………32
第五章 討論……………………………………………….………..33
5-1 砷暴露與癌症之劑量效應關係………………………33
5-2 肝癌病人上皮生長因子受體之變異…………………37
5-3 其他癌症之上皮生長因子受體表現…………………38
5-4 研究限制……………………………………………….40
第六章 結論與建議……………………………………………….41
6-1 結論………………………………………………………41
6-2 建議………………………………………………………42
參考文獻………………………………………………….………….59
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