儘管胃癌的發生呈現全球性的減少，其發生率及死亡率仍分別為台灣癌症發生率的第八位（2003年）及死亡率的第五位（2005年）。在多細胞真核生物體內一種由基因調控的細胞死亡稱作細胞凋亡，藉由啟動內在的自殺程式而移除贅生、被感染、轉形或受傷的細胞而在胚胎發育、維持免疫系統功能及組織恆定上扮演重要的機制。單核&#33527;酸多型性是遺傳變異中數量最多的一種形式且被認為是一種影響癌症風險的重要內生性因素。我們執行一個以醫院為基礎的病例對照研究，探討凋亡路徑相關基因的單核&#33527;酸多型性與胃癌的相關性。自2003年到2006年在高雄榮民總醫院，我們連續收集205名經病理證實的胃癌病患與397名健康者配對。以聚合&#37238;連鎖反應－限制&#37238;片段多型性技術分析由血液萃取的去氧核糖核酸樣本。在凋亡路徑相關的七個關鍵基因（FAS, FASL, SURVIVIN, XIAP, CASP3, CASP8, CASP9），我們分析八個單核&#33527;酸多型性的基因型，最後只有四個基因(FAS G-1377A, FAS A-670G, FASL T-844C, CASP3-A21926C, CASP9- Arg221Gln) 上的五個單核&#33527;酸多型性可有效的用於統計分析。結果顯示幽門螺旋桿菌感染（p=0.004）、抽煙（p=0.003）、喝酒（p=0.004）、常食用醃漬（p<0.001）及發酵食物（p<0.001）與胃癌具統計相關性，而喝咖啡（p=0.002）及常食用蔬菜（p=0.003）、水果（p<0.001）則具保護性。CASP3 A21926C與CASP9 codon Arg221Gln單核&#33527;酸多型性的相互作用與胃癌有統計相關性。另外，五個凋亡路徑相關基因的高危險性基因型中，若受檢者隨機攜帶三個（或多於三個）高危險性基因型會比攜帶少於三個高危險性基因型者，增加罹患胃癌的風險（p=0.027）。再者，在基因與環境因子的相互作用，我們發現CASP9 codon Arg221Gln 多型性對高齡者為危險因子，且具統計差異性（p=0.046）。隨機攜帶三種以上高危險性基因型對高齡（p=0.014）、非幽門螺旋桿菌感染（p=0.043）、不抽煙（p=0.004）、不喝酒（p=0.007）、常食用醃漬食物（p=0.014）及蔬菜（p=0.033）為危險因子，且具統計差異性（p=0.046）。根據本研究的結果顯示，細胞凋亡路徑相關基因的多型性與胃癌發生風險有顯著相關。

Gastric cancer is the second leading cause of cancer death worldwide, killing upwards of one million people each year. Apoptosis, a genetically controlled cell death in multicellular eukaryotic organisms, is an important mechanism for embryonic development, immune-system function and maintenance of tissue homeostasis through activation of an intrinsic suicide program to eliminate superfluous, infected, transformed or damaged cells. Single nucleotide polymorphism (SNP) is the most abundant type of genetic variations and is considered to be an important endogenous cause and fundamental factor influencing cancer risk. We conducted a hospital-based case-control study to investigate the association between apoptosis related genes and the risk for gastric cancer. We continuously enrolled 205 patients with pathologically proved gastric cancer and 397 frequency-matched healthy controls at Kaohsiung Veterans General Hospital from 2003 to 2006. Blood derived DNA samples from all participants were genotyped by PCR-RFLP to identify eight SNPs on seven key genes (FAS, FASL, SURVIVIN, XIAP, CASP3, CASP8, CASP9) in apoptotic pathway, but only five SNPs on four genes (FAS, FASL, CASP3, CASP9) were eventually valid for subsequent analyses. Our results showed that significant effects of H. pylori infection, cigarette smoking, alcohol drinking, and consumption of salted food and fermented food on gastric cancer risk while coffee drinking and consumption of vegetables and fruits had significant protective effects against gastric cancer in our study cohort. None of the individual gene polymorphism was associated with the risk of gastric cancer. However, the gene-gene interaction between CASP3 A21926C and CASP9 codon Arg221Gln polymorphisms was significantly associated with gastric cancer risk. In the combined analysis of four apoptosis related genes, our data showed that individuals carrying three or more putative high-risk genotypes were significantly associated with the development of gastric cancer than those who carrying two or less putative high-risk genotypes. Besides, the CASP9 codon Arg221Gln polymorphism was a risk factor for gastric cancer in people equal to or elder than fifty, though not in people younger than fifty. Taken together, our results indicated that SNPs on apoptosis related genes were associated to the development of gastric cancer.

Part 1 1
Association of Fas Related Apoptosis Pathway Genes with the
Risk for Gastric Cancer
1. Background and Literatures review 2
2. Introduction 25
3. Aim of the study 31
4. Materials and Methods 32
5. Results 39
6. Discussions 48
7. References 55
8. Tables 83
9. Figures and Figure legends 97
Part 2 104
The Relations Among Polymorphism of Apoptosis–related
Genes, Precancerous Lesions and Growth Kinetics of Gastric Epithelium
1. Abbreviation 105
2. Abstract in Chinese 106
3. Abstract in English 107
4. Introduction 108
5. Materials and Methods 117
6. Results 128
7. Discussion 133
8. Reference 137
9. Tables 140

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