臺灣博碩士論文加值系統

(一) 全台灣及烏腳病盛行地區移行上皮癌之流行病學特徵
為了瞭解台灣及烏腳病盛行地區移行上皮癌（TCC）發生率及膀胱癌死亡率的長期趨勢、病理型態及發病年齡等流行病學特徵，以及評估年齡、年代和世代對於TCC之發生與死亡的效應，本研究收集民國六十年至八十七年的全國死亡檔案，以及民國六十八年至八十五年的全國癌症發生檔的資料進行上述之分析。結果發現不論是全台灣或是烏腳病盛行地區，TCC的發生率均呈現成長的現象。在死亡率方面，台灣地區膀胱癌維持穩定的趨勢，但烏腳病盛行地區在1981-1985年以後死亡率已有顯著下降。在發病年齡方面，全台灣以60-69歲及70-79歲所占的比例較多，各約佔TCC發病數的30﹪左右。但烏腳病盛行區的發病年齡較小，50-59歲及60-69歲所占的比例較多，分別佔TCC發病數的34﹪及42﹪。在病理型態方面，不論是全台灣或烏腳病地區的膀胱癌皆以移行細胞癌為主，且其所占比例逐年上升。腎臟及其他泌尿道器官之病理型態在全台灣以移行細胞癌及腎細胞癌為主，但烏腳病盛行區則以移行細胞癌為主，且多發生於腎盂及輸尿管。在年齡－年代－世代模式分析結果顯示，TCC的發生率或膀胱癌的死亡率皆有顯著的年齡效應。在全台灣，TCC的發生率有明顯的逐年增加之年代效應，但世代效應則不顯著；膀胱癌的死亡率之年代及世代效應皆不明顯。在烏腳病盛行區，TCC的發生率之年代效應並不顯著，但有自1896年以後出生者逐漸上升的世代效應；膀胱癌死亡率則無顯著之年代及世代效應。烏腳病盛行區相對於全台灣的TCC間接標準化發生比在1991-1996年男性為540.4，女性為630.8，且隨著年代比值變化不大；而膀胱癌的間接標準化死亡比在1996-1998年男性為952.7，女性為1152.2，且隨著年代死亡比值逐漸下降。
(二) 烏腳病盛行區及非盛行地區移行上皮癌發生之長期世代追蹤
為了評估烏腳病盛行區及非盛行區居民發生全癌症及移行上皮癌（TCC）的相對危險性，以排除生態研究可能產生的生態謬誤，並進一步控制癌症危險因子如抽菸習慣等的可能干擾作用，本研究以烏腳病盛行區的長期追蹤世代2933人及非盛行區的長期追蹤世代40642人為研究對象，來追蹤比較全癌症及移行上皮癌的發生狀況。結果發現烏腳病盛行區追蹤世代的癌症發生人數，依序為皮膚癌、膀胱癌、肺癌、肝癌及腎臟癌；而在非盛行區追蹤世代，則依序為肝癌、肺癌、結直腸癌、胃癌及子宮頸癌。在烏腳病盛行區，30歲至85歲之全癌症及TCC的累積發生率分別為男性的0.70及0.15，以及女性的0.48及0.08。非盛行區之全癌症及TCC的累積發生率分別為男性的0.33及0.011，以及女性的0.27及0.0058。在調整年齡、性別、抽菸及喝酒習慣、教育程度等因子後，烏腳病盛行區世代相對於非盛行區世代罹患全癌症及TCC的相對危險性分別達到3.95及27.23，其p值皆小於0.001。
(三) 烏腳病盛行區及非盛行區皮膚癌患者罹患內臟癌危險性之世代追蹤研究
為了闡明烏腳病盛行區皮膚癌患者相對於非盛行區皮膚癌患者，是否有較高的內臟癌發生率，本研究合併烏腳病盛行區追蹤世代以及來自全國癌症登記檔的全台灣皮膚癌患者追蹤世代共10621名為研究對象，並且追蹤其自發病日期至1996年12月31日止的內臟癌發生危險性。分析結果發現台灣皮膚癌患者、烏腳病盛行區非皮膚癌患者、烏腳病盛行區皮膚癌患者之全癌症的30歲至85歲的累積發生率，分別為0.30、0.35及0.63；膀胱癌累積發生率，分別為0.0078、0.0200及0.0812；腎臟癌之累積發生率，則為0.0149、0.0457及0.0654。若以台灣皮膚癌患者為參考組，則烏腳病盛行區非皮膚癌患之全癌症、膀胱癌、腎癌、肺癌、肝癌、大腸直腸癌的相對危險性分別為0.98、4.83、2.33、0.90、1.88及0.78；烏腳病盛行區皮膚癌患者則分別為3.06、16.59、7.19、4.28、3.95及1.50。烏腳病盛行區追蹤世代在調整累積砷暴露量之後，內臟癌、TCC及肺癌的疾病危險性仍和是否罹患皮膚癌呈現顯著相關，皮膚癌似可代表砷暴露者罹患第二原發內臟癌的易感受指標。
(四) 麩胺硫轉移酵素、乙醯轉移酵素及p53之基因多形性與罹患移行上皮癌危險性之病例對照研究
為了評估代謝酵素及抑癌基因p53的基因多形性與砷引起之移行上皮癌是否相關，本研究以民國87年起在奇美醫院進行的128名TCC病例和341名非TCC對照來進行分析。結果發現具有砷暴露者，TCC的疾病危險性和GSTM1、T1、P1、NAT2及p53均無顯著相關。對於無砷暴露或無抽菸習慣者，具有GSTM1無效基因型者有較高之罹患TCC之危險性（OR：1.6~1.8）。有抽菸習慣者若具有GSTT1無效基因型，疾病的相對危險性會升高至2.0倍。若抽菸習慣者具有GSTM1、T1中至少有一個以上為無效基因型或GSTP1為非GSTP1a*1a者，疾病的相對危險性則升高至2.4倍，且具統計顯著意義。若GSTM1、T1皆為無效型且GSTP1為非GSTP1a*1a，則疾病危險性更升高至4.6倍。這結果顯示GSTs酵素對於抽菸者發生TCC有顯著的修飾作用。至於NAT2和p53，則不論有無抽菸或砷暴露，均和疾病無顯著相關。
(五) 砷暴露與非砷暴露誘發之膀胱移行上皮癌組織之比較基因體雜交（CGH）研究
為了瞭解台灣地區膀胱移行上皮癌的癌化過程，並比較烏腳病盛行區和非盛行區之TCC組織中染色體之變化狀況，本研究自奇美醫院收集膀胱移行上皮癌組織共49個，其中來自盛行區而且與砷暴露有關的組織有24個，來自非盛行區而且與砷暴露無關的有25個。本研究利用比較基因雜交法，將腫瘤及正常DNA分別連接不同的螢光劑，再與中期染色體雜交並利用螢光顯微鏡觀察，藉按染色體上螢光比例的變化來判定DNA的漏失或增加。分析結果顯示砷暴露組與非暴露組比較，都有偏高的染色體異常人數比例（100% vs. 72%）或是染色體產生變異部位的平均數（5.71 vs. 2.88）。若以染色體異常數目作為應變項納入線性迴歸模式分析，結果顯示砷暴露的相關性最強，其次為腫瘤期數。腫瘤級數及抽菸和染色體異常之相關性不明顯。若比較砷暴露組及非暴露組，則染色體異常變化有顯著差別的區域包括1p、3q、4q、7q、8q的DNA增加及10q、16p、17p的DNA漏失。較易發生DNA漏失的部位，在非砷暴露組為9q（28.0﹪）、10q（16.0﹪），而砷暴露組為9p（25.0﹪）、9q（33.3﹪）、10q（29.2﹪）、16p（25.0﹪）、17p（41.7﹪）等。較易發生DNA增加的部位，在非砷暴露組為1p、5q及7q（12.0﹪），而砷暴露組為1p（33.3﹪）、3q（20.8﹪）、4q（29.2﹪）、7q（20.8﹪）及8q（20.8﹪）。

（1） Epidemiological Characteristics of Urinary Transitional Cell Carcinoma （TCC） in Taiwan and the Blackfoot Disease（BFD）-endemic Area
In order to compare the epidemiological characteristics, including secular trend, histological pattern and age-period-cohort effect, of TCC in Taiwan and the BFD-endemic area, we analyzed the data from the national death certification system （1971-1998）and cancer registration system（1979-1996）. The incidence of TCC has been increasing in both Taiwan and the BFD-endemic area. The mortality of TCC in Taiwan has been rather stable, but it started to decrease after 1980s in the BFD-endemic area. In Taiwan, the peak age at diagnosis of TCC was among 60-69 and 70-79 age groups, with 30% and 30% of total TCC cases respectively. The peak age was among 50-59 and 60-69 age groups in the BFD-endemic area, with percentage of 34 and 42 respectively . The major histological type of urinary bladder cancers was transitional cell carcinoma in Taiwan and the BFD-endemic area, and the percentage of TCC remained increasing. The major histological types of kidney cancer were TCC and renal cell carcinoma in Taiwan, but the only major histological type was transitional cell carcinoma in the BFD-endemic area with a dominant location of renal pelvis. The age-period-cohort analysis showed a significant age effect on the incidence of TCC and the mortality of bladder cancer in Taiwan and the BFD-endemic area. There was a significant period effect but not cohort effect on the incidence of TCC. In the BFD-endemic area, the period effect on TCC incidence was not significant with cohort effect increasing slowly. Neither the period nor the cohort effects on the mortality of bladder was significant in Taiwan and the BFD-endemic area. The indirect standardized incidence ratio (SIR) of TCC of the BFD-endemic area was 540.4 in male and 630.8 in female during 1991-1996, and the ratios remained quite stable during the followed years. The indirect standardized mortality ratio (SMR) of bladder was 952.7 in male and 1152.2 in female during 1996-1998, and the ratios were decreasing.
（2） Long-term Follow-up Study on Incidence of All Cancer Sites combined and Urinary Transitional Cell Carcinoma in Cohorts of BFD-endemic and Non-BFD endemic Areas
In order to overcome the unavoidable ecological fallacy in the ecological studies, and further to control disease-related risk factors such as cigarette smoking and educational level, we followed the cohorts both from non-BFD endemic area (40642) and BFD-endemic area (2933) to evaluate the relative risk of all cancers and urinary TCC after 12-year follow-up. Among the cohort of BFD-endemic area, the dominant cancer sites were skin, bladder, lung, liver and kidney; among the cohort of non-BFD endemic area the dominant sites were liver, lung, colonrectum, stomach and cervical. In BFD-endemic area, the cumulative incidence (30+) of all cancers and urinary TCC were 0.70 and 0.15 in male, 0.48 and 0.08 in female. In non-BFD endemic area the cumulative incidence were 0.33 and 0.011 in male, 0.27 and 0.0058 in female respectively. The cohort of non-BFD endemic area as a reference group, the relative risk of all cancers and urinary TCC were as high as 3.95 and 27.23 after adjusting for age, sex, habit of cigarette smoking and alcohol drinking, and educational level.
（3） Cohort Study on Second Primary Cancers among Skin Cancer Patients in BFD and non-BFD endemic Areas
In order to elucidate the increased cancer incidence of the skin cancer patients in BFD-endemic area, and also to determine whether a history of nonmelanoma skin cancer (NMSC) in non-BFD area predicts cancer incidence, we draw the data from the cohort of BFD-endemic area and from the data linkage of profile of national cancer registration. A total of 10621 subjects were recruited and followed to 31, December, 1996. Among the groups of the skin cancer in Taiwan (7430), non-skin cancer in BFD-endemic area (2590), and the skin cancer in BFD-endemic area (601), the cumulative incidence (30+) of all cancer sites except skin were 0.30, 0.35 and 0.63 respectively; the cumulative incidence of bladder were 0.0078, 0.0200 and 0.0812 respectively; the cumulative incidence of kidney were 0.0149, 0.0457 and 0.0654 respectively. The NMSC in Taiwan as a reference group, the relative risk of all cancers except skin, bladder, kidney, lung, liver and colonrectum were 0.98, 4.83, 2.33, 0.90, 1.88 and 0.78 among the non skin cancer patients in BFD area; and 3.06, 16.59, 7.19, 4.28, 3.95 and 1.50 among then skin cancer patients in BFD-endemic area. In the cohort of BFD-endemic area, the significant association between skin cancer and the increased risk of all cancers except skin, lung, bladder and urinary TCC was shown after adjusting for cumulative arsenic exposure and years of drinking deep-well water, implied that arsenic-induced skin cancer was a significant predictive marker for second primary cancer incidence.
（4） Case-control Study on genetic polymorphism of Glutathione S-transferase (GSTs), N-acetyl transferase 2 (NAT2) and p53 and Risk of Urinary Transitional Cell Carcinoma
To evaluate the relationship between GSTM1, GSTT1, GSTP1, NAT2 and p53 gene polymorphism and the risk of urinary TCC, we proposed the case control study in Chi-Mei Hospital from 1998. It was shown that among the subjects with arsenic exposure, all the markers described above were not related to the risk of urinary TCC. Among the subjects with neither arsenic exposure nor habit of cigarette smoking, the persons with GSTM1 null type had increased TCC risk ( OR: 1.6~1.8). The odd ratio of disease in the subjects with habit of cigarette smoking and with GSTT1 null type, the odd was 2.0. Among the smoking subjects with at least one null type among GSTM1, GSTT1 or with non-GSTP1a*1a genotype, the odd ratio of disease increased to 2.4. If the smoking subjects had both GSTM1 and GSTT1 null type and non-GSTP1a*1a genotype, the OR increased as high as 4.6. The result confirmed the significant modification of GSTs to cigarette-induced urinary TCC. On the other hand, NAT2 and p53 were not associated with risk of urinary TCC no matter the exposure of cigarette or arsenic.
（5） Comparative Genomic Hybridization (CGH) Study on Bladder Transitional Cell Carcinoma in Arsenic-endemic and Non-endemic Areas
In order to realize the carcinogenesis of bladder TCC in Taiwan, and to compare the differences of chromosomal abnormality between arsenic and non-arsenic related TCC, we analyzed 24 arsenic-related TCC tumors and 25 non-arsenic related tumors from Chi-Mei Hospital by CGH. The principle of CGH is to conjugate the tumor and normal DNA with different fluorescence by nick translation, and hybridize to the metaphase chromosome for 72 hours. According to the fluorescence ratio we decide the location of gene losses and gains. Our result showed that in the arsenic-related group, the percentage of tumor samples with at least one chromosomal abnormality（100﹪vs. 72﹪）, as well as the average numbers of abnormal locus in one sample（5.71 vs. 2.88）, were significantly higher than those of non-arsenic related tumors. The linear regression showed the strongest association between arsenic exposure and the average numbers of abnormal locus in one sample. The stage of tumor also showed the significant association, but not cigarette smoking and tumor grade. The significant difference between arsenic and non-arsenic related tumors were DNA gains of 1p, 3q, 4q, 7q and 8p; DNA losses of 10q, 16p, 17p. The most frequent sites for DNA losses in non-arsenic related group were 9q（28.0﹪） and 10q（16.0﹪），in arsenic related group were 9p（25.0﹪）, 9q（33.3﹪）, 10q（29.2﹪）, 16p（25.0﹪）, 17p（41.7﹪）。The most frequent sites for DNA gains in non-arsenic related group were 1p, 5q and 7q（12.0﹪），in arsenic related group were 1p（33.3﹪）, 3q（20.8﹪）, 4q（29.2﹪）, 7q（20.8﹪） and 8q（20.8﹪）。

目　　錄
致　　謝…………………………………………………………………
I
中文摘要…………………………………………………………………
II
英文摘要…………………………………………………………………
VIII
目　　錄…………………………………………………………………
XV
圖表目錄…………………………………………………………………
XXI
第一章　　前　　言…………………………………………………
1
第二章　　文獻探討…………………………………………………
4
　1　膀胱癌之描述性流行病學特徵…………………………………4
　　1.1　發生率之國際比較…………………………………4
　　1.2　長期趨勢…………………………………………………6
　　1.3　病理類型…………………………………………………8
　　1.4　台灣的流行病學特徵……………………………………………
9
　2　膀胱癌的危險因子…………………………………………………11
　　2.1　抽菸…………………………………………………11
　　2.2　職業暴露…………………………………………………12
　　2.3　染髮劑…………………………………………………15
　　2.4　咖啡…………………………………………………16
　　2.5　人工甘味劑…………………………………………………16
　　2.6　營養攝取…………………………………………………17
　　2.7　服用藥物…………………………………………………18
　　2.8　泌尿道疾病…………………………………………………19
　　2.9　尿液滯留…………………………………………………20
　　2.10 游離輻射…………………………………………………20
　　2.11 飲用水的氯化副產物…………………………………21
　　2.12 無機砷暴露…………………………………………………
22
　3　膀胱癌與個人遺傳易感受性…………………………………27
　　3.1　概　　述…………………………………………………27
　　3.2　NAT酵素與膀胱癌…………………………………………28
　　3.3　GSTs酵素與膀胱癌…………………………………………30
　　3.4　其他代謝酵素與膀胱癌…………………………………37
　　3.5　p53基因多形性與膀胱癌…………………………………38
　　3.6　研究的限制
…………………………………39
　4　膀胱癌致癌機轉及染色體變異的研究現況……………………40
　　4.1　分子遺傳模式…………………………………………………40
　　4.2　比較基因雜交法（CGH）的作用原理及優缺點…………45
　　4.3　膀胱癌的CGH研究…………………………………………
48
　5　臺灣地區的研究現況…………………………………………
51
第三章 台灣及烏腳病盛行地區移行皮癌之流行病學特徵 …………………………………………………
55
　1　前　　言…………………………………………………
55
　2　材料與方法…………………………………………………56
　　2.1　研究資料來源…………………………………………………56
　　　2.1.1　行政院衛生署之全國癌症登記檔……………………56
　　　2.1.2　行政院衛生置死因診斷登記檔……………………57
　　　2.1.3　內政部台閩地區人口統計……………………57
　　2.2　烏腳病盛行地區患者之定義……………………57
　　2.3　移行上皮癌之定義……………………57
　　2.4　統計方法…………………………………………………56
2.4.1 年齡標準化移行上皮癌發生率和膀胱癌死亡率57
2.4.2 性別年齡別累積死亡率和發生率及各年代年齡別死亡及發生 ……………………………………………………
58
2.4.3 年齡標準化發生比（SIR）或死亡比（SMR）……………59
2.4.4 年齡－年代－世代分析模式……………………60
2.4.5 國際膀胱癌發生率的比較……………………
61
　3　研究結果…………………………………………………61
3.1 台灣及烏腳病盛行地區移行上皮癌及膀胱癌之描述性
特徵 …………………………………………………
………
61
3.1.1　移行上皮癌發生率趨勢……………………61
　3.1.2　膀胱癌死亡率趨勢……………………64
　3.1.3　人口學特徵……………………67
　3.1.4　組織型態之分布……………………79
3.2 烏腳病盛行地區相對於台灣地區間接標準化移行上皮癌發生比及膀胱癌死亡比 ……………………………83
3.3 台灣及烏腳病盛行地區之移行上皮癌發生率及膀胱死亡率之年齡、年代、世代分析 ……………………………3. 85
3.4　國際比較及不同地區華人比較……………………
93
　4　討　　論……………………
96
第四章 烏腳病盛行區及非盛行區移行上皮癌發生之長期世代追蹤研究………………………………
103
　1　前　　言…………………………………………………
103
　2　材料與方法…………………………………………………104
　　2.1　研究對象…………………………………………………104
　　　2.1.1　烏腳病盛行區長期追蹤世代……………………104
　　　2.1.2　重大疾病危險因子（MRMD）長期追蹤世代…………105
　　　2.1.3　癌症篩檢小組（CSP）長期追蹤世代……………………106
　　2.2　疾病之定義…………………………………………………107
　　2.3　研究方法…………………………………………………107
　　　2.3.1　問卷資料蒐集…………………………………………107
　　　2.3.2　個人之砷暴露評估指標……………………107
　　　2.3.3　疾病資料的蒐集及人年的計算……………………108
　　　2.3.4　資料分析…………………………………………………
109
　3　結　　果…………………………………………………
110
　4　討　　論…………………………………………………
128
第五章 烏腳病盛行區與非盛行地區皮膚砷癌患者罹患內臟癌危險性之世代追蹤研究 ………………………
135
　1　前　　言…………………………………………………
135
　2　材料與方法…………………………………………………136
　　2.1　追蹤世代…………………………………………………136
　　2.2　資料分析…………………………………………………138
　3　結　　果…………………………………………………
139
　4　討　　論…………………………………………………
153
第六章 麩胺硫轉移酵素、乙醯轉移酵素及p53基因多形性與移行上皮癌相關性之病例對照研究 …………
160
　1　前　　言…………………………………………………
160
　2　材料與方法…………………………………………………161
　　2.1　研究個案…………………………………………………161
　　2.2　問卷訪視…………………………………………………162
　　2.3　血液之收集…………………………………………………163
　　2.4　實驗分析…………………………………………………163
　　　2.4.1　DNA萃取…………………………………………………163
　　　2.4.2　GSTM1基因多形性測定……………………………165
　　　2.4.3　GSTT1基因多形性測定……………………………166
　2.4.4　GSTP1基因多形性測定……………………………167
　　　2.4.5　NAT2基因多形性測定……………………………167
　　　2.4.6　p53基因多形性測定……………………………169
　　2.5　資料建檔…………………………………………………170
　　2.6　統計分析…………………………………………………
171
　3　結　　果…………………………………………………
172
　4　討　　論…………………………………………………
185
第七章 砷暴露及非砷暴露誘發之膀胱移行上皮癌組織之比較基因體雜交法研究 ………………………………
190
　1　前　　言…………………………………………………
190
　2　材料與方法…………………………………………………192
　　2.1　個案及檢體…………………………………………………192
　　2.2　腫瘤DNA萃取……………………………192
　　2.3　比較基因雜交法……………………………194
　　　2.3.1　螢光標記染色體之製作……………………………194
　　　2.3.2　染色體雜交液的製備……………………………195
　　　2.3.3　中期抹片的雜交……………………………196
　　　2.3.4　抹片的沖洗……………………………196
　　　2.3.5　數位式影像分析……………………………197
　　　2.3.6　CGH結果的解釋……………………………197
　　　2.3.7　控制實驗…………………………………………………199
2.4 統計分析
……………………………199
　3　結　　果…………………………………………………
199
　4　討　　論
…………………………………………………212
參考文獻…………………………………………………220
圖表目錄
圖2-1 比較性基因雜交法的簡圖說明………………………………………46
圖3-1 台灣地區及烏腳病地區1979年至1996年各年代男女性移行上皮癌(TCC)之年齡標準化發生率 ……………………………………63
圖3-2 台灣地區及烏腳病地區1971年至1998年各年代男女性膀胱癌之年齡標準化死亡率………………………………………………………… 65
圖3-3 台灣地區及烏腳病地區1971年至1998年各年代男女性腎臟及其他泌尿道癌之年齡標準化死率…………………………………………… 67
圖3-4 1991年至1996年台灣地區及烏腳病地區性別年齡別之移行上皮癌累積發生率 ……………………………………………………68
圖3-5 台灣地區男性年齡別移行上皮癌每十萬人口發生率………………69
圖3-6 台灣地區女性年齡別移行上皮癌每十萬人口發生率 ……………69
圖3-7 烏腳病地區男性年齡別移行上皮癌每十萬人口發生率 …………72
圖3-8 烏腳病地區女性年齡別移行上皮癌每十萬人口發生率 …………72
圖3-9 1996年至1998年台灣地區及烏腳病地區性別年齡別之膀胱癌累積
死亡率 ………………………………………………………………73
圖3-10 1996年至1998年台灣地區及烏腳病地區性別年齡別之腎臟及其他泌尿道癌累積死亡率 ………………………………………… 74
圖3-11 台灣地區男性年齡別膀胱癌每十萬人口死亡率……………………76
圖3-12 台灣地區女性年齡別膀胱癌每十萬人口死亡率……………………76
圖3-13 烏腳病地區男性年齡別膀胱癌每十萬人口死亡率…………………78
圖3-14 烏腳病地區女性年齡別膀胱癌每十萬人口死亡率…………………78
圖3-15 台灣地區1979年至1996年膀胱癌病理組織別百分率……………79
圖3-16 烏腳病地區1979年至1996年膀胱癌病理組織別百分率…………80
圖3-17 台灣地區1979年至1996年腎臟及其他泌尿道癌病理組織別百分率 …………………………………………………………………81
圖3-18 烏腳病地區1979年至1996年腎臟及其他泌尿道癌病理組織別百分率 ……………………………………………………………………81
圖3-19a 台灣地區移行上皮癌發生率之年齡效應 …………………………87
圖3-19b 台灣地區移行上皮癌發生率之年代效應 …………………………87
圖3-19c 台灣地區移行上皮癌發生率之世代效應 …………………………87
圖3-20a 烏腳病地區移行上皮癌發生率之年齡效應 ………………………88
圖3-20b 烏腳病地區移行上皮癌發生率之年代效應 ………………………88
圖3-20c 烏腳病地區移行上皮癌發生率之世代效應 ………………………88
圖3-21a 台灣地區膀胱癌死亡率之年齡效應…………………………………91
圖3-21b 台灣地區膀胱癌死亡率之年代效應…………………………………91
圖3-21c 台灣地區膀胱癌死亡率之世代效應…………………………………91
圖3-22a 烏腳病地區膀胱癌死亡率之年齡效應 …………………………… 92
圖3-22b 烏腳病地區膀胱癌死亡率之年代效應 …………………………… 92
圖3-22c 烏腳病地區膀胱癌死亡率之世代效應 …………………………… 92
圖3-23 1988年至1992年世界各國及台灣男女性膀胱癌之
年齡標準化發生率……………………………………………………94
圖3-22 1988年至1992年世界各地區華人膀胱癌年齡標準化發生率
之比較…………………………………………………………………95
圖4-1 烏腳病及非烏腳病地區世代之性別年齡別全癌症累積發生率… 117
圖4-2 烏腳病及非烏腳病地區世代之性別年齡別膀胱癌累積發生率… 118
圖4-3 烏腳病及非烏腳病地區世代之性別年齡別移行上皮癌累積發生率 …………………………………………………………………118
圖5-1 烏腳病盛行區皮膚癌患、非皮膚癌患、台灣地區皮膚癌患及一般族群之全癌症、大腸直腸癌、肝癌、肺癌、膀胱癌、腎臟癌及移行上皮癌之三十歲以上累積發生率………………………………………………146
圖7-1 CGH分析中在螢光顯微鏡下所觀察的中期染色體圖及經5-10個染色體平均所得之DNA漏失及增加的情形。左邊紅線代表DNA漏失，右邊綠線代表DNA增加 ………………………………………………198
圖7-2 非砷暴露者之染色體基因變化結果。左邊的線代表DNA漏失，右邊的線代表DNA增加 ……………………………………………… 204
圖7-3 砷暴露者之染色體基因變化結果。左邊的線代表DNA漏失，右邊的線代表DNA增加 ………………………………………………… 205
圖7-4 砷暴露及非砷暴露者用比較基因雜交法所得之DNA增加(gains)的百分比 ………………………………………………………………… 209
圖7-5 砷暴露及非砷暴露者用比較基因雜交法所得之DNA漏失(losses)的百分比 ………………………………………………………………… 210
圖7-6 砷暴露及非砷暴露者DNA漏失情形(losses)與世界各國CGH研究之比較 ……………………………………………………………………214
圖7-7 砷暴露及非砷暴露者DNA增加情形(gains)與世界各國CGH研究之比
較 ……………………………………………………………………215
表2-1 國內外砷與膀胱癌相關之流行病學研究………………………………25
表2-1 國內外砷與膀胱癌相關之流行病學研究（續） ……………………26
表2-2 膀胱癌與氮-乙醯轉移酵素（NAT）基因多形性之相關研究……… 31
表2-2 膀胱癌與氮-乙醯轉移酵素（NAT）基因多形性之相關研究（續）…32
表2-3 膀胱癌與麩氨硫轉移酵素(GST)基因多形性之相關研究 …………35
表2-4 膀胱癌的染色體變異研究…………………………………………… 42
表2-5 基因異常與膀胱癌臨床表徵之關聯性…………………………………43
表2-6 以CGH分析膀胱癌DNA增加（gains）或漏失（losses）的研究……………………………………………………………………… 49
表2-6 以CGH分析膀胱癌DNA增加（gains）或漏失（losses）的研究（續）………………………………………………………………… 50
表3-1 台灣地區及烏腳病地區1979年至1996年各年代男女性每十萬人口泌尿道移行上皮癌之年齡標準化發生率………………………………… 63
表3-2 臺灣地區及烏腳病地區1979年至1996年各年代30歲以上男女性每十萬人口移行上皮癌之年齡標準化發生率…………………………… 64
表3-3：台灣地區及烏腳病地區1971年至1998年各年代男女性每十萬人口膀胱癌和腎臟癌及其他泌尿道癌之年齡標準化死亡率 ………………66
表3-4 台灣地區1979年至1996年移行上皮癌每十萬人口之年齡別發生率………………………………………………………………………70
表3-5 烏腳病地區1979-1996年移行上皮癌每十萬人口之年齡別發生率………………………………………………………………………71
表3-6 台灣地區1971年-1998年膀胱癌每十萬人口之年齡別死亡率…… 75
表3-7 烏腳病地區1971年-1998年膀胱癌每十萬人口之年齡別死亡率… 77
表3-8 台灣地區及烏腳病地區ICD9為189之部位別分布比例………… 82
表3-9 烏腳病地區相對於台灣地區移行上皮癌之間接標準化發生比（SIR）……………………………………………………………… 83
表3-10 烏腳病地區相對於台灣地區膀胱癌之間接標準化死亡比(SMR) …84
表3-11 台灣及烏腳病地區移行上皮癌發生率年齡年代世代分析模式之相對危險性估計值 …………………………………………………86
表3-12 台灣及烏腳病地區膀胱癌死亡率年齡年代世代分析模式之相對危險性估計值…………………………………………………………………90
表4-1 烏腳病及非烏腳病地區追蹤世代之人口學特徵 …………………112
表4-2 烏腳病及非烏腳病地區追蹤世代至1996年底之癌症分布……… 113
表4-2 烏腳病及非烏腳病地區追蹤世代至1996年底之癌症分布（續）…114
表4-3 烏腳病及非烏腳病地區追蹤世代全癌症、膀胱癌及移行細胞癌之性別標準化發生率及累積發生率 ……………………………… 116
表4-4 以非烏腳病追蹤世代為標準人口所計算烏腳病追蹤世代全癌症、膀胱癌及移行細胞癌之間接標準化發生率比值(SIR) ……………………119
表4-5 烏腳病地區相對於非烏腳病地區追蹤世代全癌症、膀胱癌及移行細胞癌調整危險因子後之相對危險性…………………………………………120
表4-6 非烏腳病地區追蹤世代全癌症、膀胱癌及移行細胞癌危險因子之單變項分析 ……………………………………………………………………122
表4-7 非烏腳病地區追蹤世代全癌症、膀胱癌及移行細胞癌危險因子之多變項分析……………………………………………………………………… 123
表4-8 烏腳病地區追蹤世代全癌症、膀胱癌及移行細胞癌危險因子之單變項分析 ………………………………………………………………………124
表4-9 烏腳病地區追蹤世代全癌症危險因子之多變項分析…………………126
表4-10 烏腳病地區追蹤世代膀胱癌危險因子之多變項分析…………………127
表4-11 國內外無機砷與膀胱癌相關研究和本分結果之比較 ………………130
表5-1 烏腳病地區皮膚癌患、非皮膚癌患及台灣地區皮膚癌患的基本變項
分佈 …………………………………………………………… 139
表5-2 烏腳病地區皮膚癌患、非皮膚癌患及台灣地區皮膚癌患追蹤期間的癌症發生分佈 ……………………………………………………………141
表5-3 烏腳病地區皮膚癌患、非皮膚癌患及台灣地區皮膚癌患各癌症的間接標準化發生比（SIR）-- 以1994年台灣發生率族群為標準 ………142
表5-4 烏腳病地區皮膚癌患、非皮膚癌患、台灣地區皮膚癌患及一般族群全癌症、大腸直腸癌、肝癌、肺癌、膀胱癌、腎癌及移行上皮癌之每十萬人年三十歲以上標準化發生率及累積發生率 ………………… 145
表5-5 以台灣非烏腳病地區皮膚癌患為參考組所求得烏腳病地區皮膚癌患及非皮膚癌患之性別、年齡調整之大腸直腸癌、肝癌、肺癌、膀胱癌、腎癌、移行上皮癌及全癌症之相對危險性及95﹪信賴區間
………………………………………………………………………… 147
表5-6 烏腳病地區皮膚癌患、非皮膚癌患、台灣地區皮膚癌患及一般族群肝癌、肺癌、膀胱癌及腎癌的組織型態分佈……………………………149
表5-7 烏腳病地區追蹤世代全癌症、大腸直腸癌、肝癌、肺癌、膀胱癌及移行上皮癌危險因子之多變項分析（1） ……………………………… 150
表5-8 烏腳病地區追蹤世代全癌症、大腸直腸癌、肝癌、肺癌、膀胱癌及移行上皮癌危險因子之多變項分析（2） ……………………………… 151
表5-9 台灣地區皮膚癌患之全癌症、大腸直腸癌、肝癌、肺癌、膀胱癌及移行上皮癌年齡和性別效應之分析……………………………………… 152
表5-10 國外針對非黑色素皮膚癌患罹患第二癌症的追蹤研究…………… 154
表6-1 奇美醫院移行上皮癌病例及醫院對照之人口學變項分布情形
………………………………………………………………………… 173
表6-2 奇美醫院移行上皮癌病例及醫院對照以砷暴露之有無分組的人口學變項分布情形 ……………………………………………………………174
表6-3 奇美醫院移行上皮癌病例及醫院對照以抽菸之有無分組的人口學變項分布情形 ………………………………………………………………175
表6-4 奇美醫院移行上皮癌病例及其醫院對照之GSTM1、T1、P1、p53、NAT2基因型分佈情形 ……………………………………………………176
表6-5 以砷暴露有無分組之GSTM1、T1、P1、p53、NAT2基因型與移行上皮癌危險性之單變項分析 ………………………………………………177
表6-6 以抽菸習慣有無分組之GSTM1、T1、P1、p53、NAT2基因型與移行上皮癌危險性之單變項分析 ………………………………………… 177
表6-7 移行上皮癌危險性與GSTM1﹑T1﹑P1﹑NAT2及p53基因型相關性的複迴歸分析(1) …………………………………………………… 179
表6-8 以砷暴露有無分組之GSTM1、T1、P1基因型組合與移行上皮癌危險性之單變項分析 ……………………………………………………… 180
表6-9 以抽菸習慣有無分組之GSTM1、T1、P1基因型組合與移行上皮癌危險性之單變項分析 …………………………………………………… 181
表6-10 以砷暴露有無分組之GSTM1、T1、P1、NAT2基因型組合與移行上皮癌危險性之單變項分析 …………………………………………… 183
表6-11 以抽菸習慣有無分組之GSTM1、T1、P1、NAT2基因型組合與移行上皮癌危險性之單變項分析 ………………………………………… 183
表6-12 移行上皮癌危險性與GSTM1﹑T1﹑P1基因型組合及NAT2及p53相關性的複迴歸分析 ………………………………………………… 184
表7-1 以砷暴露之有無為分組之描述性特徵及病理特徵………………… 201
表7-2 依砷暴露、抽菸、級數及期數分組之DNA增加或漏失人數分布及比例 ………………………………………………………………… 202
表7-3 依砷暴露、抽菸、級數及期數分組之DNA增加或漏失的個數及標準差 ………………………………………………………………… 203
表7-4 以染色體異常數目為因變項的線性模式分析……………………… 203
表7-5 所有研究對象之年齡、性別、病理特徵及DNA增加或漏失的情形
……………………………………………………………………… 206
表7-5 所有研究對象之年齡、性別、病理特徵及DNA增加或漏失的情形
（續）……………………………………………………………… 207
表7-6 砷暴露及非砷暴露者DNA增加或漏失之百分比(%)………………208
表7-7 膀胱移行上皮癌DNA增加及DNA漏失頻率較高部位的分組分析
……………………………………………………………………… 211
表7-8 本研究中較常被發現染色體變異位置所在的致癌及抑癌基因一覽表
……………………………………………………………………… 217

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