背景： 肺癌是台灣女性之首要癌症死因。近三十年來，台灣男女性肺癌幾乎都增加八倍，是世界上增加最快的地區。性比例約保持在1.6-2.3，屬於世界最低的地區。女性肺癌病人只有9-10%吸菸，而族群中女性吸菸率僅3-4%。這些流行病學特徵都顯示除了主動吸菸外，應該還有其他危險因子扮演重要角色。烹飪油煙，二手菸，女性荷爾蒙，及遺傳易罹癌性都是可能的危險因子。
材料及方法：第一個研究是世代追蹤研究，其目的在於探討吸菸對台灣各種主要疾病之相對危險性及可歸因死亡人數。一共收案14,397名四十歲以上之男女，分別來自台灣的十二個鄉鎮，收案時間是1982-1986。主要收集香菸及其他重要危險因子之暴露狀態。追蹤時間至1994年為止。第二個研究是病例對照研究，主要探討台灣地區女性肺腺癌之可能危險因子。總共收案184名新發女性肺腺癌病例及350名健康對照。研究個案均接受結構式問卷訪談調查，其內容包括吸菸及二手菸暴露、烹飪油煙暴露、月經史、懷孕史、個人病史、及家族病史；並且探討各種易感受基因之多形性和女性肺腺癌之關係。本研究探討之基因多形性包括第一階段異物代謝酵素如細胞色素P4501A1、1A2、1B1、2C19及2E1；第二階段異物代謝酵素如GSTM1、GSTT1、GSTP1，NAT1、NAT2、EH及COMT；及女性荷爾蒙接受器及代謝酵素如CYP1A1、CYP17、CYP19、ESR及COMT。一共有147名新發女性肺腺癌及267名健康對照組接受基因型之鑑定。
結果：世代追蹤研究發現，吸菸會增加男性的全死因(RR=1.3)、所有癌症(RR=1.5)、胃癌(RR=1.9)、肝癌(RR=2.2)、肺癌(RR=3.7)、缺血性心臟病(RR=1.8)、其他心臟病(RR=1.4)及慢性阻塞性肺病(RR=1.9)的死亡危險性。抽菸會增加女性的全死因(RR=1.8)、肺癌(RR=3.6)及消化性潰瘍(RR=17.8)的死亡危險性。估計台灣一年死於吸菸者，男性約有8161人(13.9%)，女性約有1216人(3.3%)。
病例對照研究發現，菸煙暴露(OR=2.0)、用動物油煮食 (OR=2.0)、口服避孕藥(OR=0.6)、女性荷爾蒙補充治療(OR=0.2)、身體質量指數BMI(OR=0.5)、及停經狀況(OR=9.8)都與女性肺腺癌有統計顯著相關。在第一階段異物代謝基因的複迴歸模式中，我們發現CYP1A2多形性(GG/GA vs. AA)有統計顯著意義(OR=6.5)。若將CYP1A1、CYP1A2、CYP2E1之危險基因型合併分析，其基因劑量效應也達邊際統計顯著水準(p=0.06)。若將吸菸、烹飪油煙、及危險基因多形性合併分析，則發現危險因子數目越多，女性肺腺癌危險性越高之顯著劑量效應關係。具備有上述三項危險因子者比三項危險因子皆無者，罹患女性肺腺癌的危險性高達20.8倍。在第二階段異物代謝酵素基因多形性的複迴歸分析中，我們發現COMT (Met/Met, Met/Val vs. Val/Val, OR=2.2)、EH (Tyr/Tyr vs. Tyr/His, His/His, OR=2.0) 與女性肺腺癌之相關達統計顯著水準。若將COMT、EH、GSTM1之危險基因型合併分析，發現擁有三項危險基因型者罹患女性肺腺癌的相對危險性高達三項危險基因型皆無者的11.7倍，同時呈現顯著之劑量效應關係(p<0.001)。基因及環境暴露之合併分析，也呈現統計顯著的劑量效應關係。在NAT1及NAT2的合併分析中，具有一或二個快速乙醯化基因型的人比兩者皆屬慢乙醯化基因型的人有較高的風險，其相對危險性高達8.4倍。在女性荷爾蒙接受器及代謝酵素基因多形性複迴歸分析中，我們發現COMT (Met/Met, Met/Val vs. Val/Val, OR=1.7)、CYP17 (A2/A2 vs. A1/A1, OR=2.2)均與女性肺腺癌有統計顯著相關。而COMT和CYP17之危險基因型對於女性肺腺癌具有加成到相乘之交互作用，且其交互作用會受到 BMI 及女性荷爾蒙暴露期間之修飾。
結論：在世代研究中，我們發現在台灣59%的男性肺癌可歸因於吸菸，但僅有10%的女性肺癌可歸因於吸菸，因此可能有其他之危險因子也會導致肺癌之發生。在病例對照研究中，我們發現二手菸及烹飪油煙仍然是重要的外在危險因子。然而本研究卻發現內源性及外源性之女性荷爾蒙濃度也會影響女性肺腺癌之發生。較高的女性荷爾蒙濃度，或較長期的女性荷爾蒙暴露均具有保護女性肺腺癌之作用。我們提出下列假說來解釋：「三十年來台灣女性肺腺癌之增加，主要導因於增加外在暴露(如烹飪油煙及二手菸)和華人較低的女性荷爾蒙濃度所產生之交互作用」。此交互作用之生理機轉有兩種可能性：(1)女性荷爾蒙在不同之濃度具有促進氧化或抗氧化之作用，進而修飾外在環境暴露之致癌作用。(2)環境暴露的許多物質會誘導CYP1A1、CYP1A2、CYP1B1等酵素活性，進而加速女性荷爾蒙之代謝。我們也發現CYP1A2、 NAT1、NAT2和女性肺腺癌之發生有較高的相關性，這結果強烈暗示著中式烹飪之油煙暴露中所產生的多環胺(heterocyclic amines, HAAs)及二手菸中的芳香胺( aromatic amines)是女性肺腺癌之主要致癌物。油煙所含多環胺會誘導CYP1A2在肺臟及肝臟之表現。使得多環胺臟肝臟或肺部經CYP1A2代謝，形成氮- 基多環胺( N-hydroxyl HAAs)，然後在於肺部經由NATs 進行氧乙醯化(O-acetylation)，最後形成 DNA鍵結物，而產生肺腺癌。我們發現COMT和CYP17對於女性肺腺癌之發生會呈現加成到相乘之交互作用，而且進一步受到 BMI 及女性荷爾蒙暴露時間之修飾。此結果與女性肺腺癌和荷爾蒙相關因子有顯著相關之結果一致，再次肯定女性肺腺癌與女性荷爾蒙有關。大規模的病例對照研究及家族研究可以朝此方向進行。

Background: Lung cancer is the leading cancer death among women in Taiwan since 1986. In Taiwan, the increasing secular trend of lung cancer mortality in past thirty years was highest in the world showing an eight-fold increase. The male-to-female ratio of lung cancer mortality in Taiwan was the lowest (1.6-2.3) compared with other countries. The prevalence of active cigarette smoking for lung cancer patients and general population in Taiwanese women was also the lowest in the world. These epidemiological findings suggest some risk factors other than active smoking may play a major role in the development of female lung adenocarcinoma in Taiwan. Cooking fumes exposure, passive tobacco smoke, hormonal factors, and genetic susceptibility were suspected factors.
Methods: In the first study, we examined the relative risk of dying from various diseases for cigarette smoking and annual mortality attributable to cigarette smoking in Taiwan. A cohort of 14,397 male and female residents aged 40 years or older recruited from 12 townships and precincts in Taiwan from 1982 to 1986. Information on cigarette smoking was collected from each subject at local health centers through a standardized personal interview based on a structured questionnaire. They were followed up regularly to determine their vital status until 1994. In the second study, we investigated the potential risk factors for female lung adenocarcinoma. We recruited a total of 184 incident female patients with lung adenocarcinoma from National Taiwan University Hospital and 350 healthy controls from hospital health examinees from National Taiwan University Hospital. Data on risk factors, including tobacco smoke exposure, cooking fume exposure, hormone-related risk factors, personal medical history and family history of lung cancer were obtained from standardized interview based on a structured questionnaire. In this study, we investigated the association with female lung adenocarcinoma for genetic polymorphisms of xenobiotic metabolism enzymes and estrogen receptor. The included phase I xenobiotic metabolism enzymes including CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2C19; phase II xenobiotic metabolism enzymes including GSTM1, GSTT1, GSTP1, NAT1, NAT2, EH, COMT; and estrogen receptor and metabolism enzymes, including CYP1A1, CYP17, CYP19, ESR, and COMT. The genotyping was carried out on 148 incident cases of female lung adenocarcinoma and the 267 healthy controls.
Results: In the cohort study, cigarette smoking was significantly associated with an increased risk of dying from all causes combined (RR= 1.3), cancer of all sites combined (RR = 1.5), stomach cancer (RR = 1.9), liver cancer (RR = 2.2), lung cancer (RR = 3.7), ischaemic heart disease (RR = 1.8), other heart diseases (RR = 1.4), and chronic obstructive pulmonary disease (RR = 1.9) among men. Among women, cigarette smoking was significantly associated with an increased risk of dying from all causes combined (RR = 1.8), lung cancer (RR = 3.6), and peptic ulcer (RR = 17.8). The estimated number of deaths attributable to cigarette smoking in Taiwan was 8161 (13.9% of total deaths) for men and 1216 (3.3% of total deaths) for women.
In the case-control study, cooking with lard (OR=2.0), use of oral contraceptives (OR=0.6), hormone replacement therapy (OR=0.2), body mass index (OR=0.5), tobacco smoke exposure (OR=2.0), and menopause (OR=9.8) were all statistically significantly associated with lung adenocarcinoma in the multiple logistic regression analysis. Among phase I xenobiotic metabolism enzymes, only CYP1A2 was significantly associated with development of female lung adenocarcinoma (GG/GA vs. AA, OR=6.5). In the analysis of combinatory effects of high-risk genotypes of, CYP1A1, CYP1A2, and CYP2E1, a borderline significance was found (p test for trend=0.06) for the dose-response relationship. In further analysis of gene-environment interaction, women who had three putative high-risk environmental and genetic factors were strongly associated with lung adenocarcinoma (OR=20.8) compared with referent group with no high-risk factors. In the multiple logistic regression analysis of association with female lung adenocarcinoma for genetic polymorphisms of phase II xenobiotic metabolism enzymes, COMT (Met/Met, Met/Val vs. Val/Val OR=2.2), EH (Tyr/Tyr vs. Tyr/His, His/His, OR=2.0) were significantly associated with development of female lung adenocarcinoma. Those who had three high-risk genotypes of GSTM1, EH, and COMT had an 11.7-folds increase in risk of developing lung adenocarcinoma. There was a significant trend of female lung adenocarcinoma risk by the number of high-risk genotypes of GSTM1, EH, and COMT. A significant gene-environment interaction was also observed for phase II xenobiotic metabolism enzymes. Analysis of association between female lung adenocarcinoma and genetic polymorphisms of NAT1/NAT2, those who with one or two rapid acetylator genotypes of NAT1 and NAT2 had an 8.4-folds risk of female lung adenocarcinoma, compared with slow acetylator genotypes of both NAT1 and NAT2. In multiple logistic regression analysis of female hormone-related genetic polymorphisms, COMT (Met/Met, Met/Val, vs. Val/Val, OR=1.7), and CYP17 (A2/A2 vs. A1/A1) were significantly associated with female lung adenocarcinoma. There was an additive to multiplicative interaction between genetic polymorphisms of CYP17 and COMT on the development of female lung adenocarcinoma. The interactive effect of CYP17 and COMT was modified by body mass index and duration of female hormone exposure. There was a significant trend (p<0.005) of female lung adenocarcinoma by the number of high-risk genotypes of female hormone-related enzymes.
Conclusion: In the cohort study, we found that 59% of male lung cancers and only 10% of female lung cancers were attributable to cigarette smoking. Some risk factors other than cigarette might play an important role in the development of female lung adenocarcinoma in Taiwan. In the case-control study, we found both cooking fume and passive tobacco smoke were important external exposure associated with female lung adenocarcinoma. Furthermore, endogenous and exogenous hormone could also affect the risk for female lung adenocarcinoma. The high level of estrogen or long duration of estrogen exposure was protective factors for female lung adenocarcinoma. It is hypothesized that the increasing exposure to passive cigarette smoke and cooking fume during past thirty years might interact with endogenous hormonal factors to result in the growing epidemic of female lung adenocarcinoma in Taiwan. The etiological mechanisms of the interaction may include: 1) Estrogen might modify the carcinogenic effect of cooking fume and passive cigarette smoke through its pro-oxidant and anti-oxidant effects. The predominance of effects of lipid peroxidation or free radical scavenger depends on the level of catechol estrogen. 2) Carcinogens from cooking fume and passive cigarette smoke might act as an inducer of CYP1A1, 1A2, and 1B1. The induction might facilitate the metabolism of estrogen. In the analysis of genetic polymorphisms of xenobiotic metabolism enzymes, CYP1A2, NAT1, and NAT2 were associated with the risk of lung adenocarcinoma. The results suggest that heterocyclic amines from cooking fumes or aromatic amines from passive cigarette smoke, which are metabolized by CYP1A2 and NATs, are major carcinogens for lung adenocarcinoma. The heterocyclic amines inhaled from cooking fume may induce CYP1A2 expression in lung tissue. Initially, the heterocyclic amines were metabolized by CYP1A2 to form N-hydroxyl heterocyclic amines in the liver or lung. They may then be O-acetylated by NATs in the lung tissue, and form DNA adducts finally. Genetic polymorphisms of CYP17 and COMT were found to interact additively to multiplicatively in development of female lung adenocarcinoma, and the interactive effect was modified by BMI and hormone exposure period. The findings are compatible with the hypothesis that female lung adenocarcinoma is a hormone-related cancer.

目錄
中文摘要……………………………………………………………1
英文摘要……………………………………………………………5
第一章: 肺癌之流行病學特徵、危險因子及防治策略…………11
中文摘要…………………………………………………12
英文摘要…………………………………………………13
前言………………………………………………………14
世界各國之肺癌流行病學特徵特徵……………………14
台灣之肺癌流行病學特徵………………………………16
肺癌之危險因子…………………………………………17
防治策略…………………………………………………26
總結及展望………………………………………………33
參考文獻…………………………………………………35
圖表………………………………………………………45
第二章: 台灣地區吸菸對各主要疾病可歸因死亡之世代追蹤研究：
12年追蹤結果…………………………………………51
英文摘要…………………………………………………52
前言………………………………………………………54
材料及方法………………………………………………56
結果………………………………………………………61
討論………………………………………………………65
參考文獻…………………………………………………73
圖表………………………………………………………75
第三章: 台灣地區女性肺腺癌之危險因子………………………85
英文摘要…………………………………………………86
前言………………………………………………………89
材料及方法………………………………………………93
結果………………………………………………………98
討論………………………………………………………104
參考文獻…………………………………………………119
圖表………………………………………………………123
第四章: 台灣地區女性肺腺癌之分子流行病學研究： 第一階段異物代謝酵素基因多形性………………137
英文摘要…………………………………………………138
前言………………………………………………………140
材料及方法………………………………………………145
結果………………………………………………………150
討論………………………………………………………154
參考文獻…………………………………………………167
圖表………………………………………………………171
第五章: 台灣地區女性肺腺癌之分子流行病學研究： 第二階段異物代謝酵素基因多形性………………177
英文摘要…………………………………………………178
前言………………………………………………………180
材料及方法………………………………………………186
結果………………………………………………………191
討論………………………………………………………195
參考文獻…………………………………………………208
圖表………………………………………………………214
第六章: 台灣地區女性肺腺癌之分子流行病學研究： 女性荷爾蒙接受器及代謝酵素基因多形性………223
英文摘要…………………………………………………224
前言………………………………………………………226
材料及方法………………………………………………231
結果………………………………………………………236
討論………………………………………………………240
參考文獻…………………………………………………250
圖表………………………………………………………253

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