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    題名: 林奇氏症病人中致癌物代謝基因和環境因子與大腸直腸癌風險之相關性
    Carcinogen Metabolism Genes and Environmental Factors Associated with Colorectal Cancer Risk in Patients with Lynch Syndrome
    作者: 張峻毓
    Chang, Chun-Yu
    貢獻者: 葉志清
    關鍵詞: 林奇氏症,大腸直腸癌,錯配修復,致癌物代謝基因,基因多形性
    Lynch Syndrome,Colorectal cancer,Mismatch repair,Carcinogen metabolism genes,polymorphisms
    日期: 2016-07-22
    上傳時間: 2018-10-01 09:51:30 (UTC+8)
    摘要: 背景：
    大腸直腸癌(colorectal cancer, CRC)15%~30%是由於遺傳基因上的問題，其中林奇氏症(Lynch Syndrome)，在所有大腸直腸癌的患者中約佔1%~5%。致癌物代謝基因負責有毒物質的代謝，有毒物質攝入體內後，像是多環芳香烴(polycyclic aromatic hydrocarbons, PAHs)與多環胺類(heterocyclic amines, HCAs)，依據代謝的不同可分為第一期與第二期酵素，像是cytochrome P450酵素、N-乙醯基轉移酶(N-acetyltransferases, NATs)和穀胱甘肽S轉移酶(Glutathione S-transferases, GSTs)，這些酵素的基因上具有高度的變異性。有很多研究探討致癌物質代謝基因與偶發性大腸直腸癌的相關性，但對遺傳性大腸直腸癌的文章很少被探討。
    目的：
    探討致癌物代謝基因(GSTs、NAT1、NAT2、CYP1A1、CYP1A2)的基因多形性在林奇氏症族群發生大腸直腸癌的角色。
    方法：
    自2000年5月至2012年2月，根據阿姆斯特丹標準，收集台灣七家醫院招募的林奇氏症病患，總共有251位帶有錯誤配對修補(mismatch repair, MMR)基因突變且確定為MLH1與MSH2的突變者，其中有127位是大腸直腸癌患者。GSTT1、GSTM1基因多形性是利用聚合酶連鎖反應(polymerase chain reaction，PCR)分析，GSTP1、NAT1、NAT2、CYP1A1、CYP1A2利用Sequenom iPLEX MassArray來分析。校正家族關係的Cox’s proportional hazard model判斷不同基因型和罹患大腸直腸癌的風險比(hazard ratio, HR)和95%信賴區間(confidence interval, CI)。
    結果：
    校正性別、突變基因、家族聚集和大腸鏡篩檢出良性腫瘤並切除後GSTM1、GSTT1、GSTA1、NAT1、NAT2、CYP1A1*2C和CYP1A2*1F基因與林奇氏症家族發生大腸直腸癌的風險沒有相關性，而GSTP1 Ile105Val帶有AG基因型，對林奇氏症發生大腸直腸癌具有顯著相關，具有保護作用，HR為0.62 (95% CI=0.39-0.99)，相反的GSTP1帶有AA基因型比起AG+GG基因型，對於大腸直腸癌會稍微增加危險性(HR=1.51, 95% CI=0.97-2.34, P=0.067)，尤其是在蔬菜攝取量低的對象 (HR=2.33, 95% CI=1.22-4.46, P=0.011)。另外，相對於帶有CYP1A1*MspI TC+TT基因型，帶有CC基因型對林奇氏症發生大腸直腸癌具有顯著危險性，HR為2.24 (95% CI=1.12-4.48)。
    結論：
    在林奇氏症家族中，GSTP1 Ile105Val和CYP1A1*MspI基因形性可能是發生大腸直腸癌的危險因子。
    Background:
    There are 15%~30% colorectal cancer (CRC) patients due to hereditary problem. Lynch Syndrome contributes to about 1%~5% of all CRC patients. Carcinogen metabolism genes responsible for the detoxification of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs). This biotransformation process involves phase I and phase II enzymes. The genes encode the metabolizing enzymes, such as cytochrome P450, N-acetyltransferases (NAT), and Glutathione S-transferases (GSTs), are highly variant. Many studies have investigated the association between polymorphisms in carcinogen metabolism genes and risk of sporadic CRC, but studies on Lynch Syndrome related CRC are rare.
    Aims:
    The aim of this study was to investigate the role of the carcinogen metabolism genes in CRC risk among Lynch Syndrome patients.
    Methods:
    From May 2000 to February 2012, according to the Amsterdam criteria II, we enrolled Lynch Syndrome patients from seven hospitals in Taiwan. A total of 251 MMR (mismatch repair) mutation carriers were identified by either mutated MLH1 or MSH2 genes and 127 patients have CRC development. Polymorphisms for GSTT1, GSTM1, GSTP1, NAT1, NAT2, CYP1A1, and CYP1A2 were determined by PCR methods or Sequenom iPLEX MassArray. A Cox proportional hazard model adjusted for family correlation was used tocalculate the hazard ratio (HR) and 95% confidence intervals (CI) to determine the association between polymorphisms and CRC risk.
    Result:
    After adjusted with sex, MMR mutation, family cluster, and colonoscopy screening, no significant association between GSTM1、GSTT1、GSTA1、NAT1、NAT2、CYP1A1*2C and CYP1A2*1F polymorphisms and CRC risk was observed. But in GSTP1 Ile105Val gene, patients with the AG genotype has a significantly reduced risk of CRC than those with the AA genotyoe (HR=0.62；95% CI=0.39-0.99). Conversely, compared to the GSTP1 AG+GG genotype, the AA genotype was associated with slightly increased risk of CRC (HR=1.51, 95% CI=0.97-2.34, P=0.067), particularly in patients consuming low vegetables (HR=2.33, 95% CI=1.22-4.46, P=0.011). In addition, the CYP1A1*MspI CC genotype, compared with the TC+TT genotype, exerted an increased risk of CRC in Lynch Syndrome (HR=2.24; 95% CI=1.12-4.48, P=0.023).
    Conclusion:
    In the Lynch Syndrome patients, the GSTP1 Ile105Val and CYP1A1*MspI polymorphisms may be risk factors for the development of CRC.
    描述: 碩士論文
    指導教授-葉志清
    委員-薛玉梅
    委員-唐瑞平
    資料類型: thesis
    顯示於類別:[公共衛生學系暨研究所] 碩博論文

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