The Impact of Genetic Polymorphisms of Alcohol Metabolizing Enzymes on Risk of Upper Aerodigestive Tract Cancers

研究背景: 上呼吸消化道鱗狀上皮細胞癌，包括口腔、咽部、喉部及食道黏膜腫瘤，為全球常見惡性腫瘤之一。這些惡性腫瘤與抽菸、喝酒及嚼檳榔習慣有密切的相關性，且儘管多種治療方式的進步，但是頭頸部癌與食道癌的預後及存活率仍然欠佳。釐清上呼吸消化道致癌機轉並且發展新的預防及早期癌發現的方式與策略，對於減少此區域的惡性腫瘤於健康影響的程度是相當重要的。 研究目的: 本研究的目的在於找出台灣族群中，酒精代謝酶基因多型性與上呼吸消化道癌症發生的關聯性，並討論基因與環境之間的交互作用對於癌症風險之影響。 研究方法: 這是一個以醫院基礎(hospital-based)的病例對照(case-control)候選基因(candidate gene)研究，120例頭頸部以及138例食道鱗狀上皮細胞癌症的患者，以及276例無此區域腫瘤之健康個體納入研究分析，在取得病人書面同意後，經上消化道影像強化內視鏡(image-enhanced endoscopy)檢查研究個體之上呼吸消化道，並且利用問卷方式記錄臨床資料與致癌物質使用情形，所有個體都接受週邊靜脈血液採集；利用the International HapMap Project資料庫與the National Center for Biotechnology Information之資訊，找出漢民族於酒精去氫酶(alcohol dehydrogenase)-1B、-1C，及 乙醛去氫酶(aldehyde dehydrogenase)-2基因上，γ2≧0.8之單一核苷酸基因多型性單體型標籤(haplotype tag single nucleotide polymorphism)，來研究其基因多型性與上呼吸消化道癌症風險之關係。而基因型鑑定方式則利用高流通量(high throughput)的介質輔助雷射脫附游離飛行式質譜儀系統Sequenom MassARRAY system來進行實驗。 研究結果: 低身體質量指數、抽菸、喝酒與嚼檳榔為上呼吸消化道癌症的獨立危險因子，其勝算比分別為0.78 (95%信賴區間 0.70-0.86), 7.04 (95%信賴區間3.34-14.83), 5.56 (95%信賴區間2.70-11.47)及12.46 (95%信賴區間4.65-33.39)。酒精去氫酶-1B與-1C基因的常見單倍體基因型(haplotype) GAGC (勝算比 1.61， 95% 信賴區間1.08-2.41)，及乙醛去氫酶基因的單倍體基因型CCAATG (勝算比 1.69， 95% 信賴區間1.24-2.30)會增加罹癌的風險。酒精去氫酶-1B 在rs1229984位置與乙醛去氫酶-2在rs671位置的對偶基因與上呼吸消化道癌症發生有密切相關性，而且在頭頸部與食道癌患者個體觀察到類似的現象。與帶有一般風險基因型且無致癌物質使用習慣者相比較，酗酒者如果帶有ADH1B及ALDH2的風險基因時，其罹癌風險勝算比分別為53.44 (95% 信賴區間 25.21-113.29)及70.08 (95% 信賴區間33.65-145.95)；而倘若沒有致癌物質的暴露，單純帶有風險基因型者其罹癌機會並沒有顯著增加的情形。此外，與帶有原始一般風險基因型且有致癌物質暴露史者相比較，倘若個體同時帶有ADH1B及ALDH2風險基因型，且有酗酒習慣加上抽菸或嚼檳榔時， 其食道癌及頭頸部癌症罹患風險增加為10.36倍 (95% 信賴區間3.46-31.00)及3.32倍 (95% 信賴區間 1.07-10.32)。 結論: 對致癌物質習慣性使用者而言，酒精去氫酶-1B及乙醛去氫酶-2 兩者的基因變異為重要的危險基因型，對於上呼吸消化道癌症的次級預防醫學對策來說相當重要；而研究也觀察到癌症相關的單倍體基因型。在這個研究結果當中顯示，研究疾病相關基因多型性的方法中，利用候選基因(candidate gene)的標籤單核苷酸多型性(tag single nucleotide polymorphisms)來做關聯性探討是一種有效率的研究方法，且本研究結果也支持了上呼吸消化道黏膜的癌域理論 (field cancerization)。Background Squamous cell carcinoma of the upper aerodigestive tract (UADT), including the malignancies of the oral cavity, pharynx, larynx and esophagus, is one of the most common cancers worldwide. Such malignancies are associated with the behaviors of alcohol consumption, cigarette smoking and betel quid chewing. They are with grave prognosis despite multidisciplinary therapies. Elucidation of carcinogenesis and development of novel strategies for cancer prevention and early detection are crucial for reducing the disease burden of these devastating diseases. Aims We aim to investigate the effects of genetic polymorphisms in alcohol-metabolizing enzymes on UADT cancer risk by haplotype tag single nucleotide polymorphisms (SNPs) approaching method, and to evaluate the gene-environmental interaction in Taiwanese population. Methods In this hospital-based case-control candidate gene study, 138 esophageal and 120 head and neck squamous cell carcinoma patients, and 276 controls without these malignancies after endoscopy evaluation were enrolled for study. Demographic and the status of carcinogen consumption were recorded by questionnaires. All study subjects received image-enhanced endoscopy for the evaluation of UADT cancers and blood sampling from peripheral veins. Utilizing the databases of the International HapMap Project and the National Center for Biotechnology Information, haplotype tag SNPs of the population Han Chinese in the three genes, alcohol dehydrogenase (ADH)-1B, ADH-1C, and aldehyde dehydrogenase(ALDH)-2 which have aggressive taggingγ2≧0.8 were selected for analysis. Screened SNPs were genotyped by the high throughput method, Sequenom MassARRAY system, with high resolution. Results: Lower body mass index, alcohol drinking, cigarette smoking, and betel quid chewing were independent risk factors for UADT cancers with the odds ratios (ORs) of 0.78 (95% confidence interval (CI) 0.70-0.86), 7.04 (95% CI 3.34-14.83), 5.56 (95% CI 2.70-11.47), and 12.46 (95% CI 4.65-33.39), respectively. Common haplotype GAGC (OR 1.61, 95% CI 1.08-2.41) of ADH1B and ADH1C genes on chromosome 4, and CCAATG (OR 1.69, 95% CI 1.24-2.30) of ALDH2 gene on chromosome 12 were found to increase UADT cancer risk. Risk alleles of ADH1B (rs1229984) and ALDH2 (rs671) were closely associated with UADT cancers. Similar effects were observed for both head and neck and esophageal cancers. Alcohol drinkers with risk alleles of ADH1B and ALDH2 had increased risk for UADT cancers with the ORs of 53.44 (95% CI 25.21-113.29) and 70.08 (95% CI 33.65-145.95) when compared with non-users without genetic risk factors. Without carcinogen exposure, carrying risk alleles were not associated with increased risk. Compared with subjects carrying ancestral alleles with carcinogens use, those carrying both risk alleles of ADH1B and ALDH2 with alcohol and/or cigarette and/or betel quid use had 10.36-fold (95% confidence interval (CI) 3.46-31.00, p