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The polymorphisms of UGT1A7 and UGT1A10 among Taiwan lung cancer patients.
No full text研究生口試委員會審定書 i
博碩士論文電子檔案上網授權書 ii
博碩士論文授權書 iii
中文摘要 iv
英文摘要 vi
誌謝 vii
目錄 viii
第一章 文獻回顧 1
第一節 肺癌簡介 1
第二節 致癌物質代謝酵素 2
第三節UGTs 簡介 4
第二章 研究目的 9
第三章 材料與方法 10
第一節 檢體收集 10
第二節 實驗材料 10
第二節專用儀器 12
第四節 實驗步驟與方法 17
第四章 結果 36
第五章 討論 39
第一節 臺灣UGT1A7基因多行性與其他族群比較 39
第二節 UGT1A10 codon 605流行率 39
第三節 UGT1A10 codon 693流行率 39
第四節 UGT1A7與UGT1A10 SNPs 之間的linkage 40
第五節UG1A7、UGT1A10與UGT1A1 SNPs之間的linkage 41
第六章 結論 43
參考文獻 44
附錄 53
表1. 民國92年臺灣地區主要癌症死亡原因 53
表2-1. Natural or mutagenesis primers, restriction enzymes and
the results for UGT1A7 variations 54
表2-2. Natural or mutagenesis primers, restriction enzymes and
the results for UGT1A7 variations 55
表3. Natural or mutagenesis primers, restriction enzymes and
the results for UGT1A10 variations 56
表4. 肺癌血液檢體與正常對照組的基本資料 57
表5. 肺癌組織檢體與非肺癌對照組的基本資料 57
表6. 血液檢體的UGT1A10-693基因分佈檢定 58
表7. 血液檢體的UGT1A10-605基因分佈檢定 58
表8. 組織檢體的UGT1A10-693基因分佈檢定 59
表9. 血液檢體UGT1A7 genotypes 的相對風險檢定 60
表10. 血液檢體UGT1A7 allele 的相對風險檢定 61
表11. The correlations between UGT 1A7 and UGT1A10 SNP 62
表12. The correlations between UGT 1A7, UGT1A10 and UGT1A1 SNP 63
表13. OR and 95% CI for lung cancer associated with suspected 64
gene risk factors
表14. Allele frequencies of UGT1A7 gene among ethnic groups 65
表15. UGT1A10 SNP 66
圖1. Lung cancer分類 67
圖2. UGT1As member 68
圖3. UGT 1A10 605 RFLP 69
圖4. UGT 1A10 693 RFLP 70
圖5. UGT 1A7 -57 RFLP 71
圖6. UGT 1A7 33 RFLP 72
圖7. UGT 1A10 387 RFLP 73
圖8. UGT 1A10 391 RFLP 75
圖9. UGT 1A10 392 RFLP 76
圖10.UGT 1A10 622 RFLP 77
圖11. UGT1A7 -56、33 基因訂序圖 78
圖12. UGT1A7 387、391、392、622 基因訂序圖 79
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陳建仁：台灣重要癌症之分子流行病學研究，第二十九屆國軍軍醫學術研討會專題討論專刊，2002
國家衛生研究院：肺癌臨床指引，2004.
陳慶峰：高速公路收費人員細胞色素P4501A1、尿苷二磷酸-葡萄糖醛酸轉移酶1A7及穀胱甘肽硫轉移酶M1基因多形性對尿中代謝物1-羥基芘葡萄糖苷酸濃度影響之研究，國防醫學院公共衛生學研究所碩士論文，2003.
劉晉宏：中國人UGT1A1基因多型性的研究，成功大學要理學研究所碩士論文，1999.
廖育晴：台灣肺癌患者人類乳突瘤病毒 16/18 之可能感染路徑之研究，中山醫學大學毒理學研究所，2001.[[abstract]]UDP-glucuronosyltransferase (UGT) superfamily這個家族的酵素可將內生與外生性的脂溶性化合物進行葡萄糖醛酸化，增加其水溶性，以便排出體外。UGT1A7與UGT1A10一般被認為於呼吸消化道中表現。由於先前的一些相關研究，我們已了解到酵素基因若發生序列的改變，會造成酵素的產量或代謝活性發生變化，影響酵素的解毒效率， 進而影響肺癌的發生率。
本研究將以PCR-RFLP與基因定序的方式，偵測台灣已知具有高度流行率的3種UGT1A7基因多型性，以及2個在黃種人身上具有高流行率的UGT1A10 SNP在台灣肺癌患者與健康人之間的流行率，並預期這兩個代謝重要致癌物質Benzo(a)pyrene(BaP)的PhaseⅡ代謝酵素可能會是重要的肺癌易感基因。
研究結果顯示，正常人對照組於UGT1A10 codon 693突變點的出現頻率高於肺癌病人，在血液檢體的部分，具有UGT1A10 codon 693 突變者，罹患肺癌的(odds ratio, OR)是沒有突變者的0.267倍，其(95% confidence interval, 95%C.I.)為 0.097〜0.787 (P=0.011)；在組織檢體的部分，結果仍發現非肺癌病患的UGT1A10 codon 693突變率也高於肺癌病患，並達顯著差異，OR = 0.312，95%C.I.為 0.117〜0.827 (P=0.015)。此外在UGT1A10 codon 693與UGT1A7 codon -57，33，622之間具有負相關頃向，但未達顯著意義。而UGT1A7 -57、33、622與387、391、392是具有相關性的 (r=0.52，p<0.0001)。將UGT1A10 693不突變,而UGT1A7 622突變的歸列一組，UGT1A10 693突變,而UGT1A7 622不突變的歸列一組，經計算後發現到UGT1A10 693不突變,而UGT1A7 622突變的這群人罹患肺癌的相對危險比是UGT1A10 693突變,而UGT1A7 622不突變這群人的8.77倍(95%信賴區間為 1.10〜070.0，P=0.02)顯示這兩個基因具有協同作用。
由於UGT1A10是一個代謝毒物的保護性酵素，而UGT1A10 codon 693突變是屬於靜默突變，此突變本身並不會造成酵素活性的改變，因此假設UGT1A10 codon 693可能與其他會造成UGT1A10酵素活性升高的SNP具有連鎖不平衡之現象 (linkage disequilibrium)，因此出現在正常人族群的比例明顯高於肺癌病患組。
The superfamily of UDP-glucuronosyltransferase (UGT) catalyze glucuronidation reaction, the most important process that increase substrate solubility in water and aids in their excretion by addition of sugars to fat-soluble chemicals both drugs and other xenobiotic carcinogens. Previous data suggest that UGT1A7 and UGT1A10 genetic polymorphisms may affect the enzyme production and metabolism function, therefore influence enzyme detoxification, contributes to cancer oncogenesis.
In the study, we hypothesized that both enzymes are involved in the formation of lung cancer. A hospital-base molecular epidemiology with 56 cases and 80 controls was conducted by using PCR-RFLP and DNA sequencing to compare the prevalence of three UGT1A7 and two UGT1A10 single nucleotide polymorphisms (SNPs) of lung cancer patients to non-cancer controls.
The results showed that lung cancer is associated with the mutation of UGT1A10 codon 693 regardless of the kind of samples. The odds ratio (OR), 95% confidence interval (95%C.I.), and P value of lung cancer cases versus non-cancer controls are 0.276 (0.097-0.787; P=0.011) and 0.312 (0.117-0.827; P= 0.015) in blood and lung-tissue samples respectively. No association was observed on the UGT1A10 codon 605 and three UGT1A7 polymorphisms genotype between cases and controls. The nucleotide changes of UGT1A7 at position 387, 391, 392 and -57, 33, 622 were in linkage in another variant haplotype. The nucleotide changes of UGT1A7 at position -57, 33, and 622 showed significant correlation with position 387, 391, and 392 (r=0.52, p<0.0001). The nucleotide changes of UGT1A10 at position 693 showed negative but not significant correlation with position -57, 33, and 622.
The results of this study indicate that 693 variants in the UGT1A10 genes are at lower risk to develop lung cancer may partially linking and results from other UGT1A10 SNP
