臺灣博碩士論文加值系統

酒精為引起腸胃道疾病的一個重要危險因子，在人體內主要經由
醇脫氫酶 (ADH2) 將乙醇代謝成乙醛，再由醛脫氫酶 (ALDH2) 將乙醛代謝成乙酸，因此本研究將探討飲酒，酒精代謝酵素醇脫氫酶和醛脫氫酶之基因多型性與食道癌及胃癌之相關性。
本研究設計採用醫院為主的病例對照研究法，自民國89年8月至93年6月，收集台大醫院及高雄榮民總醫院與高雄醫學大學附設中和醫院，經由醫生診斷確定為新發生食道癌之患者330位為病歷組，其對照組來自相同醫院的健康檢查，診斷無癌症病史之個案共592位；並收集來自高雄醫學大學附設中和醫院，新發生胃癌之患者140位為病歷組，其對照組來自相同醫院的健康檢查，診斷無癌症病史之個案共383位；並以年齡 (±4歲) 及性別進行配對 (病歷組：對照組=1:1~4)。利用聚合脢連鎖反應方法判斷ADH2與ALDH2基因型。
本研究在調整過有關的干擾因子之後，結果發現個案帶ADH2*1/*1基因型者，相較於帶ADH2*2/*2基因型者，罹患食道癌的危險性為3.99倍 (95%CI, 2.13-7.48)；同時，個案帶ALDH2*1/*2 及 ALDH2*2/*2基因型者，相較於帶ALDH2*1/*1基因型者，罹患食道癌的危險性分別為4.99及 4.24倍 (95% CI, 3.11-7.99 及 1.52-11.84)，並進一步發現ADH2及ALDH2的基因多型性與飲酒習慣對於食道癌的發生存在交互作用。但是，並未發現ADH2與ALDH2的基因多型性與胃癌的發生有顯著相關性。
本研究結果顯示酒精代謝酵素 (ADH2與ALDH2) 的基因多型性會調節酒精代謝而影響食道癌之發生，但是與胃癌則未有顯著的相關性。

In this study, we investigated the association between the genetic polymorphisms of ADH2 and ALDH2 and esophageal and gastric cancer risks in the Taiwanese population. A hospital-based case-control study was conducted in Taiwan. Between August, 2000 and June, 2004, 330 newly-diagnosed esophageal squamous cell carcinoma and 592 controls were recruited from National Taiwan University Hospital (NTUH), Kaohsiung Medical University Hospital (KMUH) and Kaohsiung Veterans General Hospital (KVGH). In addition, 140 newly-diagnosed gastric cancer and 383 controls were recruited from KMUH. Controls were matched to the cases by age (±4 years) and sex (cases: controls=1: 1~4). The ADH2 and ALDH2 polymorphisms were genotyped by the method of PCR-RFLP.
Individuals with ADH2*1/*1 had a 3.99-fold risk (95% CI = 2.13-7.48) to develop esophageal cancer than those with ADH2*2/*2, after adjusted for appropriate covariates. Individuals with ALDH2*1/*2 and ALDH2*2/*2 had 4.99- (95% CI = 3.11-7.99) and 4.24-fold risk (95% CI = 1.52-11.84), respectively, to develop esophageal cancer than those with ALDH2*1/*1, after adjusted for appropriate covariates. We also found an interactive risk of lifetime alcoholic consumption and genotypes (ADH2 and ALDH2) on esophageal cancer risk. Similar significant effects of ADH2 and ALDH2 on esophageal cancer risk were also found, when categorized by different drinking statuses. In contrast, no significant effect of those two polymorphisms on gastric cancer risk was noted. Those results suggest that ADH2 and ALDH2 polymorphisms play a pivotal role to modify the effect of lifetime alcohol consumption on esophageal cancer, but not on gastric cancer risk.

第一章 緒論 …………………………………………… 1
第一節 研究背景與動機 …………………………………………… 1
第二節 研究目的 …………………………………………… 2
第二章 文獻探討 …………………………………………… 3
第一節 酒精代謝過程 …………………………………………… 3
第二節 酒精代謝酵素介紹 …………………………………………… 3
第三節 酒精與癌症發生之相關研究 …………………………………………… 5
第四節 酒精代謝酵素之分子流行病學研究 …………………………………………… 6
第三章 材料與方法 …………………………………………… 8
第一節 研究方法概述 …………………………………………… 8
第二節 研究對象描述 …………………………………………… 8
第三節 問卷資料與血液檢體收集 ………………………………………… 9
第四節 實驗分析方法 …………………………………………… 9
第五節 統計分析方法 …………………………………………… 13
第四章 結果 …………………………………………… 15
第一節 食道癌結果描述 …………………………………………… 15
第二節 胃癌結果描述 …………………………………………… 21
第五章 討論 …………………………………………… 23
第一節 研究方法與個案選取 …………………………………………… 23
第二節 酒精代謝酵素與癌症發生之相關性 …………………………………………… 24
第三節 酒精代謝酵素及環境因子相互影響食道癌之關係 …………………………………………… 26
第四節 環境因子與胃癌發生的相關性 …………………………………………… 28
第五節 研究限制 …………………………………………… 32
第六節 結論 …………………………………………… 33

Bosron, W. and Li, T. (1986) Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism. Hepatiology 6, 502-510.
Chen, C., Lu, R., Chen, Y., Wang, M., Chang, Y., Li, T. and Yin, S. (1999) Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am. J. Hum. Genet. 65, 795-807.
Chen, M. J., Chiou, Y. Y., Wu, D. C. and Wu, S. L. (2000) Lifestyle Habitas and Gastric Cancer in a Hospital-Based Study in Taiwan. THE AMERICAN JOURNAL OF GASTROENTEROLOGY 95, 3242-3249.
Chen, W., Loh, E., Hsu, Y., Chen, C., Yu, J. and Cheng, A. (1996) Alcohol-metabolising genes and alcoholism among Taiwanese Han men: Independent effect of ADH2, ADH3 and ALDH2. In Br. J. Psychiatry., Vol. 168, pp. 762-767.
Crabb, D., Edenberg, H., Bosron, W. and Li, T. (1989) Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity: The inactive ALDH22 allele is dominant. J. Clin. Invest. 83, 314-316.
Enomoto, N., Takase, S., Yasuhara, M. and Takada, A. (1991) Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol. Clin. Exp. Res. 15, 141-144.
Fang, J. and Vaca, C. (1997) Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis 18, 627-632.
Farres, J., Wang, X., Takahashi, K., Cunningham, S., Wang, T. and Weiner, H. (1994) Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase. A model to study human (Oriental type) class 2 aldehyde dehydrogenase. J. Biol. Chem. 269, 13854-13860.
Goedde, H., Agarwal, D., Fritze, G., Meier-Tackmann, D., Singh, S., Beckmann, G., Bhatia, K., Chen, L., Fang, B., Lisker, R., Paik, Y., Rothhammer, F., Saha, N., Segal, B., Srivastava, L. and Czeizel, A. (1992) Distribution of ADH2 and ALDH2 genotypes in different population. Hum. Genet. 88, 344-346.
Harada, S. and Zhang, S. (1993) New strategy for detection of ALDH2 mutant. Alcohol Alcohol. 28, 11-13.
Hempel, J., Bahr-Lindstrom, H. v. and Jornvall, H. (1984b) Aldehyde dehydrogenase from human liver. Primary structure of the cytoplasmic iosenzyme. Eur. J. Biochem. 141, 21-35.
Hori, H., Kawano, T., Endo, M. and Yuasa, Y. (1997) Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and human esophageal squamous cell carcinoma susceptibility. J. Clin. Gastroenterol. 25, 568-575.
Hsu, L., Bendel, R. and Yoshida, A. (1987) Direct detection of usual and atypical alleles on the human aldehyde dehydrogenase-2（ALDH2）locus. Direct detection of usual and atypical alleles on the human aldehyde dehydrogenase-2（ALDH2）locus. 41, 996-1001.
Hung, H.-c., Huang, M.-c., Lee, J.-m., Wu, D.-c., Hsu, H.-k. and Wu, M.-t. (2004) Association between diet and esophageal cancer in Taiwan. Journal of Gastroenterology and Hepatology 19, 632-7.
IARC (1985) Allyl compounds, aldehydes, epoxides and peroxides. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. IARC 36, 101-132.
IARC (1988) Alcohol drinking. IARC Monographs on the evaluation of the carcinogenic risks to humans. IARC 44, 153-246.
Jium, C., Wang, W. and Chen, C. (1993) Helicobacter pylori infection in upper gastrointestinal diseases. Chinese J Gastroenterol 10, 115-8.
Lee, C., Lee, J., Wu, D., Hsu, H., Kao, E., Huang, H., Wang, T., Huang, M. and Wu, M. (2005) Independent and Combined Effects of Alcohol Intake, Tobacco Smoking and Betel Quid Chewing on the Risk of Esophageal Cancer in Taiwan. Int. J. Cancer. 113, 475-82.
Lee, H. H., Wu, H. Y., Chuang, Y. C., Chang, A. S., Chao, H. H., Chen, K. Y., Chen, H. K., Lai, G. M., Huang, H. H. and Chen, C. J. (1990) Epidemilogic characteristics and multiple risk factors of stomach cancer in Taiwan. Anticancer research 10, 875-882.
Matsou, Y., Yokoyama, Y. and Yokoyama, S. (1989) The genes for human alcohol dehydrogenases β1 and β2 differ by only one nucleotide. Eur. J. Biochem. 183, 317-320.
Matsuo, K., Hamajima, N., Shinoda, M., Hatooka, S., Inoue, M., Takezaki, T. and Tajima, K. (2001) Gene-environment interaction between an aldehyde dehydrogenase-2（ALDH2）polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis 22, 913-916.
Mizoi, Y., Yamamoto, K., Ueno, Y., Fukunaga, T. and Harada, S. (1994) Involvement of genetic polymorphism of alcohol and aldehyde dehydrogenases in individual variation of alcohol metabolism. Alcohol Alcohol. 29, 707-710.
Osier, M., Pakstis, A., Kidd, J., Lee, J., Yin, S., Ko, H., Edenberg, H., Lu, R. and Kidd, K. (1999) Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism. Am. J. Hum. Genet. 64, 1147-1157.
Sasazuki, S., Sasaki, S. and Tsugane, S. (2002) Cigarette smoking, alcohol consumption and subsequent gastric cancer risk by subsite and histologic type. Int. J. Cancer 101, 560-566.
Stone, C., Sorson, W. and Dunn, M. (1993) Amino acid substitutions at position 47 of Human β1β1 and β1β2 alcohol dehydrogenases affect hydride transfer and coenzyme dissociation rate constans. J. Biol. Chem. 268, 892-899.
Takeshita, T., Kawai, T. and Morimoto, K. (1997) Elevated levels of hemoglobin-associated acetaldehyde related to alcohol drinking in the atypical genotype of low Km aldehyde dehydrogenase. Cancer Res. 57, 1241-1243.
Takeshita T, M. X. a. M. K. (1996) The contribution of polymorphism in the alcohol dehydrogenase β subunit to alcohol sensitivity in a Japanese population. Hum Genet. 97, 409-413.
Thomasson, H., Edenberg, H., Crabb, D., Mai, X., Jerome, R., Li, T., Wang, S., Lin, Y., Lu, R. and Yin, S. (1991) Alcohol and Aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am. J. Hum. Genet. 48, 677-681.
Wickramasinghe, S., Gardner, B. and Barden, G. (1986) Cytotoxic protein molecules generated as a consequence of ethanol metabolism in vitro and in vivo. Lancet. 2, 823-6.
Wu-Williams, A. H., Yu, M. C. and Mack, t. M. (1990) Life-style, Workplace, and Stomach cancer by Subsite in Young Men of Los Angeles County. Cancer research 50, 2569-2576.
Wu, M., Chen, M. and Wu, D. (2004) Influences of lifestyle habits and p53 codon 72 and p21 codon 31 polymorphism on gastric cancer risk in Taiwan. Cancer Letters 205, 61-68.
Wu, M. S., Wu, C. Y., Chen, C. J., Lin, M. T., Shun, C. T. and Lin, J. T. (2003) Interleukin-10 gentypes associate with the risk of gastric cancer in Taiwanese Chinese. Int. J. Cancer 104, 617-623.
Xu, Y., Carr, L., Bosron, W., Li, T. and Edenberg, J. (1988) Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3 loci following DNA sequence amplification. Genomics 2, 209-214.
Yin, S. (1996) Alcohol dehydrogenase: Enzymology and metabolism, in "The Biology of Alcohol Problems. " J. B. Saunders and J. B. Whitfield, eds., Elsevier Science, Oxford, 113-119.
Yin, S., Chou, F., Chao, S., Tsai, S., Liao, C., Wang, S., Wu, C. and Lee, S. (1993) Alcohol and aldehyde dehydrogenases in human esophagus: comparison with the stomach enzyme activities. Alcohol. Clin. Exp. Res. 17, 376-381.
Yin, S., Han, C., Lee, A. and Wu, C. (1999) Human alcohol dehydrogenase family. Functional classification, ethanol/retinol metabolism, and medical implications. Adv. Exp. Med. Biol. 463, 265-274.
Yin, S., Wang, M., CL, H. and Wang, S. (1995) Substrate binding pocket structure of human aldehyde dehydrogenase. A sunstrate specificity approach. Adv. Exp. Med. Biol. 372, 9-16.
Yokoyama, A., Kato, H., Yokoyama, T., Tsujinaka, T., Muto, M., Omori, T., Haneda, T., Kumagai, Y., Igaki, H., Yokoyama, M., Watanabe, H., Fukuda, H. and Yoshimizu, H. (2002) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma. Carcinogenesis 23, 1851-1859.
Yokoyama, A., Muramatsu, T., Ohmori, T., Higuchi, S., Hayashida, M. and Ishii, H. (1996) Esophageal cancer and aldehyde dehydrogenase-2 genotypes in Japanese males. Cancer Epidemic. Biomark. Prev. 5, 99-102.
Yokoyama, A., Muramatsu, T., Omori, T., Matsushita, S., Yoshimizu, H., Higuchi, S., Yokoyama, T., Maruyama, K. and Ishii, H. (1999) Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics. Alcohol. Clin. Exp. Res. 23, 1705-1710.
Yokoyama, A., Muramatsu, T., Omori, T., Yokoyama, T., Matsushita, S., Higuchi, S., Maruyama, K. and Ishii, H. (2001) Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics. Carcinogenesis 22, 433-439.
Yokoyama, A., Ohmori, T., Yokoyama, T., Okuyama, K., Takahashi, H., Hasegawa, Y., Higuchi, S., Maruyama, K., Shirakura, K., Ishii, H. and Muramatsu, T. (1998) Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Carcinogenesis. 19, 1383-1387.
Yokoyama, T., Yokoyama, A., Kato, H., Tsujunaka, T., Muto, M., Omori, T., Haneda, T., Kumagai, Y., Igaki, H., Yokoyama, M., Watanabe, H. and Yoshimizu, H. (2003) Alcohol Flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men. Cancer Epidemic. Biomark. Prev. 12, 1227-1233.