臺灣博碩士論文加值系統

台灣慢性砷中毒地區在1970年代改用自來水，然而當地居民許多癌症死亡率仍高於台灣其他地區，砷皮膚癌發生率依然高居不下，顯示早期砷暴露對基因的傷害依然存在。此地區皮膚癌盛行率約為千分之5.9，也就是說並非所有暴露於無機砷者皆會發展成癌症，顯示個人對於致癌物之易感受有變異存在。
本研究以居住於台灣西南沿海皮膚癌盛行率最高之嘉義縣布袋鎮好美、復興、新民三里30歲以上居民於1988年10月至1989年6月所建立的研究世代為基礎，採重疊病例對照研究法，其中67名確診為皮膚癌病例，及242名性別、年齡配且未罹患任何癌症之健康對照。本研究將以聚合酵素連鎖反應(polymerase chain reaction, PCR)為基礎的限制片段長度多形性(restriction fragment length polymorphisms, RFLPs)進行基因形鑑定，最後以非條件對數複迴歸模式(unconditional logistic regression)模式進行單變項及多變項分析，以了解DNA修補基因(XPD、XRCC1)及麩胺基硫轉移酵素(GSTM1、GSTT1、GSTP1)對於砷皮膚癌的獨立及交互作用。
研究結果顯示GSTM1、GSTT1為無效基因型且GSTP1至少帶有一個突變對偶基因型者，罹患砷皮膚癌的危險對比值顯著高達5.7倍(95％信賴區間：1.65-19.94)。DNA修補基因XPD exon6 AC 或AA基因型者較 CC基因型者，罹患砷皮膚癌的危險對比值為 2.13 倍 (95% 信賴區間：0.95-4.76)。 DNA 修補基因XRCC1 exon9 為Arg/Arg基因型且 XPD exon6為 AC或 AA 基因型者，若和XRCC1 exon9中至少帶有一個 His基因而且 XPD exon6 為CC基因型者相比較，前者罹患砷皮膚癌的危險對比值為 2.58倍 (95%信賴區間：0.91-7.31)。
若以暴露於易感受基因的數目來分析，當以暴露於0或1個易感受基因者罹患砷皮膚癌之相對危險性對比值為1.00時，則暴露於2個易感受基因者罹患砷皮膚癌之相對危險性，在調整年齡、性別後為2.65(95%信賴區間：0.57-12.49)；則暴露於3個易感受基因者罹患砷皮膚癌之相對危險性，在調整年齡、性別後為5.87(95%信賴區間：1.31-26.37)，達計上顯著相關。

Residents in the arseniasis-endenmic area in southwestern Taiwan has started to use tap water sine 1970, the cancer mortality of them remains higher than the general population in Taiwan. The high incidence of arsenic-induced skin cancer suggests the existence of the effects of genetic damage induced by arsenic exposure in early years. The prevalence of skin cancer in this area is about 5.9 per 1,000, the low prevalence suggests the individual variation in susceptibility to arsenic- induced cancer. The specific aim of this study is to examine the association with arsenic induced skin cancer for genetic polymorphisms of glutathione S-transferase(GST) and DNA repair enzymes.
A total of 309 subjects aged 30 years and older were studied. They included 67 cases of arsenic-induced skin cancer and 242 unaffected controls. The polymerase chain reaction (PCR) with/without restriction fragment length polymorphisms (RFLPs) were used to determine genotypes. Unconditional logistic regression models were used for data analysis to assess the independent and interactive effects of DNA repair genes(XPD,XRCC1) and GST M1,T1 and P1on the development of arsenic-induced skin cancer.
Those who had at least one null or variant gene types of GST M1, T1 and P1 had an increased risk of arsenic-induced skin cancer with an odds ratio of 5.7 (95%CI, 1.65-19.94). DNA repair enzyme XPD exon6 AC or AA genotype was associated with an increased risk compared with the genotype CC showing an odds ratio of 2.13 (95%CI, 0.95-4.76). The combination of DNA repair enzyme XRCC1 exon9 genotype Arg/Arg and XPD exon6 genotypes AC or AA was found to be associated with an increased risk of arsenic-induced skin cancer showing an odds ratio of 2.58 (95%CI, 0.91-7.31) compared with the combination XRCC1 exon9 genotypes of His/His or Arg/His and XPD exon6 genotype CC.
When analyzing the risk associated with the number of susceptible genotypes of XRCC1,XPD and GST’s those who had two and three susceptible genotypes had age-sex-adjusted odds ratios of 2.65 (95%CI, 0.57-12.49) and 5.87 (95%CI, 1.31-26.37),respectively, compared with those who had none or one susceptible genotypes.

目錄
中文摘要 -----------------------------------------------------Ⅰ
英文摘要 -----------------------------------------------------II
目 錄 -----------------------------------------------------Ⅲ
第一章 前言 ---------------------------------------------- 1
第二章 文獻探討 ------------------------------------------ 3
第一節 砷之環境流布及代謝 -------------------------------- 3
1. 砷的環境流布 -------------------------------------------- 3
2. 無機砷代謝 ---------------------------------------------- 3
第二節 無機砷與皮膚之相關性研究 -------------------------- 5
1. 砷皮膚癌的臨床分類及病裡分類 ---------------------- 5
2. 飲水砷暴露與皮膚癌 -------------------------------- 6
3. 醫藥性砷暴露與皮膚癌之相關研究 -------------------- 7
4. 職業性砷暴露與皮膚癌之相關研究 -------------------- 7
5. 砷皮膚癌其他危險因子 ------------------------------ 8
第三節 砷的基因毒性 -------------------------------------- 9
第四節 DNA修補系統 ---------------------------------------10
1. DNA修補系統之功能 ---------------------------------10
2. DNA修補系統與皮膚癌之相關研究 ---------------------11
第五節 DNA修補基因XPD、XRCC1之基因多形性及其相關研究 -----13
1. DNA修補基因XPD之基因作用與基因多形性 --------------13
2. DNA修補基因XRCC1之基因作用與基因多形性 ------------13
第六節 麩胺基硫轉移酵素之基因多形性及其相關研究 ----------14
第三章 材料與方法 ----------------------------------------17
第一節 研究地區與研究世代 --------------------------------17
1. 研究地區 ------------------------------------------17
2. 研究世代 ------------------------------------------17
第二節 問卷訪視與檢體採集 --------------------------------18
1. 問卷訪視 ------------------------------------------18
2. 生物檢體採集 --------------------------------------19
第三節 皮膚癌病例之診斷及健康對照之選取 ------------------19
1. 病例的選取 ----------------------------------------19
2. 對照組選取 ----------------------------------------19
第四節 實驗方法 ------------------------------------------20
1. DNA萃取 -------------------------------------------20
2. 基因型鑑定 ----------------------------------------21
第五節 統計方法分析 --------------------------------------26
第四章 結果 ----------------------------------------------28
第五章 討論 ----------------------------------------------47
參考文獻 ---------------------------------------------------50

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