林奇氏症病人中TGF-β訊息傳導路徑基因多形性與大腸直腸癌風險的相關性

Genetic polymorphisms in the TGF-β signaling pathway associated with colorectal cancer in patients with Lynch syndrome

王彥婷(Yen-Ting Wang)

指導教授 ： 葉志清

臺北醫學大學/公共衛生暨營養學院/公共衛生學系暨研究所/碩士(2016年)

摘要

背景:林奇氏症(Lynch syndrome)大約佔所有大腸直腸癌4%的病例，是最常見的遺傳性大腸直腸癌，通常由缺陷的四個錯配修復(mismatch repair, MMR)基因遺傳，包括MLH1、MSH2、MSH6和PMS2，特別是MLH1和MSH2基因突變。而TGF-β訊息傳導路徑參與許多生物過程和疾病，包括細胞增殖、分化、遷移、凋亡及癌症，許多文獻指出TGF-β訊息傳導路徑上的基因多形性會影響癌症的風險。
目的:在林奇氏症具有MLH1和MSH2突變者中，探討TGF-β訊息傳導路徑上的TGFβ1、TGFβR1、TGFβR2和SMAD7基因多形性與發生大腸直腸癌的相關性。另外，也探討這些基因多形性是否會修飾環境因子與大腸直腸癌的相關性。
方法:本研究自2002年5月開始搜集符合阿姆斯特丹標準第二版的林奇氏症家族，收案樣本來自台灣不同地區的七所醫療機構，包含301位具有MLH1和MSH2的基因突變攜帶者，其中發生大腸直腸癌者共147人，未發生大腸直腸癌者共154人。收集病人之問卷、血液生化值檢驗資料及突變基因檢查結果。利用MassARRAY進行TGF-β訊息傳導路徑上的TGFβ1、TGFβR1、TGFβR2和SMAD7基因型的分析，再利用Cox proportional hazard regression model計算各個基因多形性的風險比(hazard ratios, HR)及其95%信賴區間(confidence intervals, CI)。
結果:在人口學變項、生活習慣和飲食習慣的多變項分析指出，客家人的風險比較高、而大腸鏡篩檢出良性腫瘤並切除及規律運動會顯著降低風險。另外，在基因多形性的分析中，只有在TGFβR2的兩個位點，分別為rs3087465和rs6785358對於林奇氏症罹患大腸直腸癌的風險有顯著相關性，在rs3087465 AG+AA vs. GG的HR為1.79 (95% CI=1.15-2.78)，在rs6785358 GA+GG vs. AA的HR為1.71 (95% CI=1.10-2.68)，皆顯著增加大腸直腸癌的風險。
結論:本研究是第一個針對林奇氏症探討TGF-β訊息傳導路徑上基因與大腸直腸癌風險的相關性。研究結果顯示TGFβR2的基因多形性會顯著增加大腸直腸癌的風險，此結果可以提供林奇氏症個案發生大腸直腸癌高風險基因風險的預防篩檢參考依據。

關鍵字

林奇氏症 ； 大腸直腸癌 ； 錯配修復基因 ； 基因多形性

並列摘要

Background: Lynch syndrome contributes to approximately 4% of all colorectal cancer (CRC) cases and is the most common hereditary colorectal cancer. It usually consisting of four mismatch repair (MMR) defects genes, MLH1, MSH2, MSH6 and PMS2, in particular, MLH1 and MSH2 gene mutation. TGF-β signaling pathway involves in many biological processes and disease, including cell proliferation, apoptosis, differentiation, migration and cancer. Many studies indicate that genetic polymorphisms on TGF-β signaling pathway may affect cancer risk.
Objective: The aim of this study was to investigate the association between genetic polymorphisms in TGF-β signaling pathway and risk of CRC among Lynch syndrome patients with MLH1 and MSH2 mutation. In addition, interactions between genetic polymorphisms and environmental factors were also explored.
Methods: This retrospective cohort study enrolled Lynch syndrome patients according to the Amsterdam criteria II from seven medical institutions in Taiwan. We identified 301 MLH1 or MSH2 gene mutation carriers, including 147 CRC cases. Polymorphisms of the genes involving in TGF-β signaling pathway, including TGFβ1, TGFβR1, TGFβR2 and SMAD7, were determined by MassARRAY. Univariate and multivariate analysis was used to analyze the association between the genetic polymorphisms and CRC risk.
Results: The multivariate analyses indicated that Hakka have higher CRC risk, but colonoscopy screening and regular exercise can significantly reduce the CRC risk. We found significant associations between TGFβR2 polymorphisms and risk of developing CRC among Lynch syndrome carries. The TGFβR2 rs3087465 (AG+AA vs. GG HR = 1.79, 95% CI=1.15-2.78) and rs6785358 (GA+GG vs. AA HR = 1.71, 95% CI=1.10-2.68) are significantly associated with increased risk of CRC.
Conclusion: This study is the first for Lynch syndrome study on TGF-β signaling pathway genes correlated with CRC risk. Our results suggested that TGFβR2 polymorphisms may associate with CRC risk among Lynch syndrome patients. Such knowledge may be helpful in identifying high-risk individuals who require more intensive surveillance.

並列關鍵字

Lynch syndrome ； Colorectal cancer ； Mismatch repair ； Genetic polymorphisms

參考文獻

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