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研究生:鄭宇凱
研究生(外文):Yu-Kai Cheng
論文名稱:晚期非小細胞肺癌患者抗藥基因多型性與病患存活之關聯性研究
論文名稱(外文):Correlation Analysis of Chemoresistant Gene Polymorphism and Survival in Patients with Advanced Non-small Cell Lung Cancer
指導教授:楊志新楊志新引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:54
中文關鍵詞:非小細胞肺癌DNA 修補基因單核苷酸點突變ERCC1XPDXRCC1XRCC3RRM1存活分析
外文關鍵詞:non-small cell lung cancerDNA repair genessingle nucleotide polymorphismSNPERCC1XPDXRCC1XRCC3RRM1survival analysis
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肺癌是我國最常見的癌症,也是國內癌症死因的第一位。雖然化學治療已成了晚期非小細胞肺癌的治療標準,然而其治療也面臨到瓶頸。為了提升治療成效,除了開發新的藥物與配方之外,篩選臨床上存活較久或反應較好的患者並找出其特性亦是一種作法。
本研究收納84位來自臺大醫院及台北榮總的晚期非小細胞肺癌患者。這些患者在確認無法治癒後至少存活兩年以上,並且在上述兩院留下完整的病歷記錄。本研究以限制酶片段長度多型性分析或直接定序測定基因多型性,並利用趨向分數降低第一次化療選擇所帶來的誤差。所有變數利用考克斯正比模型計算風險比例。研究結果發現晚期非小細胞肺癌患者存活的保護因子為帶有ERCC1 8092 G/G(HR=0.024;p=0.0013)和XRCC1 399 A/A(HR=0.007;p=0.0133)的點突變,以及帶有RRM1 2455 A/A的點突變並於第一次化療使用含有gemcitabine的藥物(HR=0.022;p=0.0056);危險因子為診斷初期即為無法治癒(HR=17.948;p=0.0005)以及帶有ERCC1 8092 T/T的高度抽菸患者(HR=102.398;p=0.0002)。
研究結果發現ERCC1 8092、XRCC1 399及RRM1 2455的點突變可影響本研究晚期非小細胞肺癌患者的存活能力。該結果雖無法拓展到整體晚期非小細胞肺患者,但可為未來研究基因點突變與晚期非小細胞肺癌患者存活之關聯性提供一個方向。
In Taiwan, lung cancer is one of the most common cancer and the leading cause of cancer-related death. Although chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC), its effect has reached a plateau. Analyzing prognostic factors and predictive factors for patients who are clinical long-survivors or better responders to systemic treatments may provide hints for future research.
In this study, we included 84 advanced NSCLC patients from National Taiwan University Hospital and Taipei Veterans General Hospital. These patients survived at least 2 years after diagnosis of incurable metastatic disease. Medical treatments are reviewed from both of above hospitals. Polymorphisms of some chemotherapy resistant associated genes were detected by either RFLP or direct sequence. We used propensity score method to reduce the bias of first-line chemotherapy, and Cox’s proportional model to estimate the hazard ratio for all variables. The protective factors identified were ERCC1 8092 G/G (HR=0.024; p=0.0013) and XRCC1 399 A/A (HR=0.007; p=0.0133) genotype, and RRM1 2455 A/A with regimens containing gemcitabine as first-line therapy (HR=0.022; p=0.0056). The risk factors are incurable disease in first-time diagnosis (HR=17.948; p=0.0005) and heavy smokers with ERCC1 8092 T/T genotype (HR=102.398; p=0.0002).
This study shows that SNPs of ERCC1 8092, XRCC1 399 and RRM1 2455 can influence survival of selected advanced NSCLC patients. Although the results may not be applicable to the whole advanced NSCLC population, further confirmation in large NSCLC population is needed.
第壹章 引言 1
第一節 非小細胞肺癌 1
第二節 化學治療在晚期非小細胞肺癌患者中扮演的角色 1
第三節 DNA修補基因在化學治療中扮演的角色 2
第四節 DNA修補基因的異常在化學治療中扮演的角色 2
1 ERCC1 3
1-1 ERCC1 8092 C>A 4
1-2 ERCC1 118 C>T 4
2 XPD 5
2-1 XPD 312 G>A及XPD 751 A>C 5
3 XRCC1 6
3-1 XRCC1 399 G>A 6
4 XRCC3 7
4-1 XRCC3 241 C>T 7
5 RRM1 8
5-1 RRM1 2464 G>A及RRM1 2455 A>G 9
第貳章 研究動機與目的 11
第參章 研究方法 12
第一節 受試者 12
第二節 受試者抗藥性基因點突變檢驗方法 12
1 檢體收集 12
2 聚合酶連鎖反應及產物純化 12
3 直接定序及限制酶片段長度多型性分析 12
第三節 臨床資料收集 13
第四節 統計方法 16
第肆章 研究結果 18
第一節 病患特徵 18
1 患者基本特徵 18
2 患者使用化療情形 20
3 患者體基因點突變分布情形 21
第二節 患者特徵與存活之關連性分析 24
第伍章 研究討論 25
第一節 初診確認無法治癒與肺癌存活之關聯性 25
第二節 ERCC1 8092點突變與肺癌存活之關聯性 25
第三節 XRCC1 399點突變與肺癌存活之關聯性 26
第四節 RRM1 2455點突變與肺癌存活之關聯性 28
第五節 研究限制 30
第六節 未來展望 31
第陸章 結論 34
第柒章 附錄 35
第一節 病患資料意義及類型 35
第二節 DNA萃取步驟 42
第三節 聚合酶連鎖反應 43
第四節 聚合酶連鎖反應產物純化 46
第五節 限制酶片段長度多型性分析 46
第捌章 參考資料 47
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