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研究生:林育弘
研究生(外文):Yu-hong Lin
論文名稱:p53和MDM2基因多型性與EGFR和K-ras基因突變在肺癌之間的關聯性
論文名稱(外文):The Relationship Between p53 and MDM2 Polymorphisms With EGFR and K-ras Mutations in Lung Cancer
指導教授:劉興璟
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱: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:2009
畢業學年度:97
語文別:中文
論文頁數:74
中文關鍵詞:基因多型性肺癌p53MDM2EGFRK-ras
外文關鍵詞:PolymorphismsLung Cancerp53MDM2EGFRK-ras
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肺癌是世界各地造成癌症死因的最主要原因,在台灣亦同。目前已知肺癌的危險因子有很多,包括吸菸、環境煙草煙霧、荷爾蒙、病毒和基因變異。許多研究指出p53和Murine double minute 2(MDM2)的某些基因型和增加癌症風險有關係。同時,Epidermal Growth Factor Receptor(EGFR)和v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(K-ras)基因突變的分布在肺癌特定族群中有著極大的差異性存在。台灣目前尚未有相關研究在p53和MDM2基因多型性與EGFR和K-ras基因突變和肺癌之間的關聯性。本研究目的是比較肺癌和對照組間之p53 codon 72和MDM2 SNP309基因型的分布,並探討p53和MDM2基因多型性與EGFR和K-ras基因突變在肺癌之間的關聯性。本研究共納入170名肺癌病患和340名正常對照組。以聚合酶連鎖反應-限制酶切割片段長度多型性(PCR-RFLP)的方式分析病患及對照組的週邊血液檢體,檢測p53 codon 72(包括Arg/Arg、Arg/Pro和Pro/Pro三種基因型)和MDM2 SNP309(包括T/T、T/G和G/G三種基因型)的基因變異,並回溯病患的病歷相關資料。研究結果顯示,p53 codon 72和MDM2 SNP309基因型分布在對照組和肺癌組之間無統計上顯著的差異(p值分別為0.35和0.72)。然而,我們發現在不吸菸之女性肺腺癌族群中,EGFR基因突變者較容易有MDM2 SNP309 G對偶基因(Odds Ratio = 2.71;95% CI = 1.10 – 6.69;p值為 0.028)。為了進一步了解肺癌中的基因因子,應該需要更進一步的研究來證實p53和MDM2基因多型性與EGFR和K-ras基因突變在肺癌之間的關聯性和機轉。
Lung cancer is the leading cause of cancer death worldwide. Similarly, it is the leading cause of cancer death in Taiwan. Risk factors for lung cancer include smoking, environmental tobacco smoke(ETS), hormonal, rival and genetic factors. Numbers of studies reported that some genotypes of p53 and Murine double minute 2(MDM2)were potentially associated with an increased risk of cancer. Furthermore, there exists a striking difference in the distribution of Epidermal growth factor receptor(EGFR)and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(K-ras) mutation in certain subgroups of lung cancer patients. However, there have been no study performed to explore the relationship between p53 and MDM2 polymorphisms, EGFR and K-ras mutations in lung cancer patients in Taiwan.
The purposes of this study were to compare the distribution of p53 codon 72 and MDM2 SNP309 genotypes between lung cancer patients and normal subjects in the Taiwanese population, and to investigate the relationship between p53 and MDM2 polymorphisms with EGFR and K-ras mutations in lung cancer.
This study included 170 lung cancer patients and 340 normal controls. Genomic DNA from peripheral blood samples was analyzed by polymerase chain reactions – restriction fragment length polymorphism(PCR-RFLP)for genetic variation in p53 codon 72 (Arg/Arg, Arg/Pro, Pro/Pro) and MDM2 SNP309 (T/T, T/G, G/G). The results showed that distribution of p53 codon 72 and MDM2 SNP309 genotypes were not significantly different between overall lung cancer and controls(p = 0.35 and p = 0.72, respectively). However, it was observed that the presence of EGFR mutation was associated with MDM2 SNP309 G allele in the non-smoker female with adenocarincoma subgroup (Odds Ratio = 2.71;95% CI = 1.10 – 6.69;p = 0.028). Further studies are warranted to investigate the relationship and mechanism between p53 and MDM2 polymorphisms with EGFR and K-ras mutations in lung cancer.
誌謝 I
中文摘要 II
英文摘要 III
目次 IV
圖目錄 VI
表目錄 VII
第1章 緒論 1
第2章 文獻探討 2
2.1 肺癌概述 2
2.1.1 肺癌簡介 2
2.1.2 肺癌的治療 5
2.1.3 肺癌的危險因子 7
2.2 抑癌基因p53 12
2.2.1 p53基因多型性 13
2.2.2 p53 codon 72基因多型性 14
2.2.3 p53 codon 72基因多型性與癌症之關係 14
2.3 致癌基因MDM2 16
2.3.1 p53和MDM2之關係 16
2.3.2 MDM2 SNP309基因多型性與癌症之關係 17
2.4 肺癌中分子特徵的變異 19
2.4.1 肺癌中p53基因突變 19
2.4.2 肺癌中EGFR與K-ras基因突變 20
第3章 研究目的 24
第4章 研究方法 25
4.1 研究設計 25
4.1.1 肺癌組與對照組之描述 25
4.1.2 病人資料收集 26
4.2 基因型檢測 27
4.2.1 p53和MDM2基因相關之定義 28
4.2.2 DNA的萃取 29
4.2.3 聚合酶連鎖反應-限制酶切割片段長度多型性 30
4.2.4 基因型的判定 33
4.3 統計方法 36
第5章 研究結果 37
5.1 基本資料 37
5.2 基因型分布 39
5.3 次族群分析(Subgroup Analysis) 42
5.3.1 肺腺癌基因型分析 42
5.3.2 年齡分析(以65歲為分層) 45
5.3.3 肺癌嚴重度分析 46
5.4 MDM2 SNP309和p53 codon 72基因型之合併分析 46
5.5 肺癌與吸菸之間的關係 46
5.6 p53及MDM2基因多型性與EGFR基因突變之間的關係 46
5.7 p53及MDM2基因多型性與K-ras基因突變之間的關係 46
第6章 討論 46
6.1 MDM2基因多型性與肺癌之關係 46
6.2 p53基因多型性與肺癌之關係 46
6.3 MDM2基因多型性與EGFR基因突變之關係 46
6.4 MDM2和p53基因型之種族差異 46
6.4.1 對照組分析 46
6.4.2 肺癌病人組分析 46
6.5 研究限制及未來改進方向 46
第7章 結論 46
參考文獻 46
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