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研究生:張仕妮
研究生(外文):Shih-Ni Chang
論文名稱:胸苷酸合成酶基因多形性與結腸直腸癌病患接受5-FU為基礎的輔助化學治療存活之相關性
論文名稱(外文):Associations between thymidylate synthase polymorphisms and survival in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapy
指導教授:宋鴻樟宋鴻樟引用關係
指導教授(外文):Fung-Chang Sung
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:環境醫學研究所碩士班
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:86
中文關鍵詞:結腸直腸癌氟尿嘧啶胸苷酸合成酶多形性存活分析
外文關鍵詞:colorectal cancer5-fluorouracilthymidylate synthasepolymorphismssurvival analysis
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氟尿嘧啶 (5-fluorouracil,簡稱5-FU)是結腸直腸癌標準且重要的化學治療藥物。5-FU的代謝產物 (5-fluorodeoxyuridylate簡稱FdUMP)會抑制TS的作用而無法合成DNA及造成細胞損傷。
TS (thymidylate synthase)基因5’端非轉譯區及3’端非轉譯區有三個常見的基因多形性被辨認出來。這些基因多形性被證實不僅會影響TS在腫瘤內mRNA表現及可能改變酵素的活性,也會影響到5-FU對於結腸直腸癌病人治療的臨床效果。本研究欲探討台灣地區5-FU為基礎化學治療的結腸直腸癌病患,其TS基因多形性對存活的相關性。
研究對象為499位於1995年至2001年被新診斷出結腸直腸癌且接受手術後5-FU化學治療的病患,並進行TS基因型鑑定。使用log-rank test 和Kaplan-Meier 存活曲線圖比較不同基因型病患存活的差別,再進一步利用Cox比例危險模式及單體型分析比較TS基因多形性與存活之相關性。
Kaplan-Meier存活曲線圖結果顯示,結腸直腸癌病患帶有3’-UTR高表現基因型有顯著較差的總存活率 (log-rank p = 0.02),女性病患或直腸癌病患也有同樣結果 (兩者的log-rank p = 0.03)。然而,在Cox比例危險模式中校正年齡和/或腫瘤分期後,總存活率沒有顯著差異。我們也發現第三期結腸直腸癌病人帶有3’-UTR ins6/ins6基因型 (HR = 1.83,95% CI = 1.04-3.21)或高表現基因型 (HR = 1.81,95% CI = 1.06-3.10)比起其他基因型有顯著較差的無病存活率。
本研究是最大型探討華人族群TS基因多形性及結腸直腸癌病患之存活相關性的研究。結果發現TS基因多形性可能是一個可以預測結腸直腸癌病人以5-FU為基礎化學治療預後的因子。
5-fluorouracil (5-FU) is one of the mainstays of standard anti-cancer drugs used in the chemotherapy for colorectal cancer (CRC). It inhibits thymidylate synthase (TS) by forming a covalent ternary complex with 5-fluorodeoxyuridylate (FdUMP) and results impaired DNA synthesis and cell death.
Three polymorphisms on the 5’-untranslated region (UTR) and 3’-UTR in the TS gene have been identified. These polymorphisms not only relate to alter intratumoral TS mRNA and protein expression, but also associate with different clinical outcomes in cancer therapy using 5-FU-based chemicals. The present study investigated whether TS polymorphisms can predict the clinical outcome of CRC patients who received 5-FU-based chemotherapy in Taiwan.
We genotyped TS polymorphisms (5’-UTR 2R/3R, 5’ G/C SNP in 3R, and 3’-UTR ins6/del6) for 499 CRC patients receiving 5-FU-based chemotherapy after surgery between 1995 and 2001. Survival analyses on TS polymorphisms were displayed with Kaplan-Meier curves and performed with log-rank test. The association between TS genotypes and survival was analyzed using Cox proportional hazard models and haplotype analysis.
The Kaplan-Meier curves showed that CRC patients with 3’-UTR high expression genotype had a significantly poor overall survival (log-rank p = 0.02), particularly for female patients and rectal cancer (both log-rank p = 0.03). However, the genetic effects on overall survival disappeared after adjustment for age and/or tumor stage in Cox proportional hazard models. We also found significantly worse disease-free survival for stage III CRC patients with 3’-UTR ins6/ins6 genotype (HR = 1.83, 95% CI = 1.04-3.21) or 3’-UTR high expression genotype (HR = 1.81, 95% CI = 1.06-3.10) than those with other genotypes.
This is the largest study to investigate the relationship between three TS polymorphisms and survival of CRC patients with chemotherapy in a Chinese population. Our findings suggest that TS polymorphisms can serve a prognostic predictor for CRC patients who receive 5-FU-based chemotherapy.
目 錄
目 錄 I
表目錄 III
圖目錄 V
中文摘要 VII
英文摘要 IX
第一章 緒論 1
第一節 研究背景與研究動機 1
第二節 研究的重要性 2
第三節 研究目的 2
第二章 文獻探討 3
第一節 結腸直腸癌的流行病學特徵 3
第二節 結腸直腸癌與化學治療 4
5-氟尿嘧啶 (5-fluorouracil,簡稱5-FU) 6
第三節 TS基因與5-FU 7
TS基因多形性 8
TS基因多形性與基因表現 11
TS基因與結腸直腸癌病人5-FU化療存活之相關性 12
第四節 結論 15
第三章 材料與方法 17
第一節 研究對象及資料來源 17
一、研究對象 17
二、基本資料及臨床診斷資料收集 17
第二節 基因型實驗分析方法 18
一、 血液檢體之收集 18
二、Genomic DNA萃取 18
三、TS基因型分析 19
第三節 資料處理與統計分析 24
一、存活分析資料定義 24
二、基因型的分組 25
三、統計檢定 26
第四章 結果 28
第一節 研究對象之描述性統計分析 28
第二節 TS基因多形性與結腸直腸癌病人化療之存活關係 30
第三節 TS基因單體型分析與結腸直腸癌化療病人之存活關係 33
第五章 討論 35
第六章 結論與建議 41
參考文獻 42





表目錄
表 1. TS的基因多形性 10
表 2. TS基因多形性與結腸直腸癌病人5-FU化療之存活相關性分析 13
表 3. 研究對象之基本資料及臨床病理變項分布 48
表 4. 研究對象之基本資料及臨床病理變項分布(依性別分) 49
表 5. 研究對象之基本資料及臨床病理變項分布 (依腫瘤位置分) 50
表 6. 研究對象之基本資料及臨床病理變項分布 (依癌症期別分) 51
表 7. 研究對象之TS基因頻率分布 52
表 8. 研究對象之TS基因頻率分布 (依性別分) 53
表 9. 研究對象之TS基因頻率分布 (依腫瘤位置分) 54
表 10. 研究對象之TS基因頻率分布 (依癌症期別分) 55
表 11. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (總存活率) 56
表 12. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (總存活率;依性別分) 57
表 13. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (總存活率;依腫瘤位置分) 58
表 14. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (總存活率;依癌症期別分) 59
表 15. 依據Cox比例危險模式計算TS基因多形性合併後之存活危險對比值 (總存活率) 60
表 16. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (無病存活率) 61
表 17. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (無病存活率;依性別分) 62
表 18. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (無病存活率;依腫瘤位置分) 63
表 19. 依據Cox比例危險模式計算TS基因多形性之存活危險對比值 (無病存活率;依癌症期別分) 64
表 20. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (總存活率) 65
表 21. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (總存活率;依性別分) 66
表 22. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (總存活率;依腫瘤位置分) 67
表 23. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (總存活率;依癌症期別分) 68
表 24. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (無病存活率) 69
表 25. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (無病存活率;依性別分) 70
表 26. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (無病存活率;依腫瘤位置分) 71
表 27. 估算TS中5’-UTR及3’-UTR所組合成單體型的危險對比值 (無病存活率;依癌症期別分) 72


圖目錄
圖 1 台灣結腸直腸癌年齡標準化發生率之長期趨勢,1995-2006年 4
圖 2 台灣結腸直腸癌治療方式百分比之長期趨勢,1996-2006年 5
圖 3 台灣結腸直腸癌化學治療百分比之長期趨勢,1995-2006年 5
圖 4 5-FU的代謝機轉 8
圖 5 TS基因多形性 10
圖 6. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in colorectal patients. 73
圖 7. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in male patients. 74
圖 8. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in female patients. 75
圖 9. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in colon cancer patients. 76
圖 10. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in rectal cancer patients. 77
圖 11. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in stage II and stage III patients. 78
圖 12. Kaplan–Meier analysis and log-rank test of the overall survival according to genotypes in stage IV patients. 79
圖 13. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in colorectal patients. 80
圖 14. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in male patients. 81
圖 15. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in female patients. 82
圖 16. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in colon cancer patients. 83
圖 17. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in rectal cancer patients. 84
圖 18. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in stage II patients. 85
圖 19. Kaplan–Meier analysis and log-rank test of the disease-free survival according to genotypes in stage III patients. 86
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