探討上皮鈣黏蛋白和內皮一氧化氮合成酶之基因多型性與肺腺癌表皮生長因子受體突變之間的關聯性

Relationship among E-cadherin gene polymorphisms, endothelial nitric oxide synthase (eNOS) gene polymorphisms, and epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma

黃俊耀(Chun-Yao Huang)

指導教授 ： 曹昌堯

中山醫學大學/醫學院/醫學研究所/博士(2019年)

https://doi.org/10.6834/CSMU201900075

摘要

EGFR突變常見於亞洲的非小細胞肺癌病人，可作為治療反應的預後因子。目前已知有一些基因多型性與癌變過程相關，如：上皮鈣黏蛋白基因CDH1、內皮一氧化氮合成酶基因eNOS。上皮鈣黏蛋白被認為是癌症轉移的關鍵步驟――上皮-間質細胞轉換過程――中的重要因子。上皮-間質細胞轉換過程與肺癌細胞株的EGFR突變以及表皮生長因子受體酪氨酸激酶抑制劑的療效相關。eNOS則在慢性發炎與癌變過程中扮演著重要的角色。本研究旨在探討肺腺癌病人的CDH1和eNOS基因多型性與EGFR突變之間的關係，及其在臨床上的影響。研究在2012至2015年間納入280位肺腺癌病人，並以即時聚合酶鏈鎖反應分析其CDH1基因多型性（rs16260和rs9929218）與eNOS基因多型性（-786 T/C和894 G/T）。結果顯示，CDH1 rs16260單核苷酸多型性的CA和CA + AA基因型與女性肺腺癌的EGFR突變呈負相關：CA基因型在校正後的勝算比為0.43，95%信賴區間為0.20–0.92；CA + AA基因型在校正後的勝算比為0.46，95%信賴區間為0.22–0.96。eNOS基因多型性的GT + TT基因型與EGFR突變（尤其是外顯子19框內缺失）呈正相關。EGFR L858R突變的次族群分析結果顯示，eNOS 894 G/T的GT + TT基因型與病人的淋巴結侵犯程度呈顯著相關。本研究結果顯示，CDH1多型性rs16260和eNOS多型性894 G/T都與肺腺癌的EGFR突變呈顯著相關。我們期待未來可將這個研究結果應用至臨床，以其作為腫瘤侵犯性或表皮生長因子受體酪氨酸激酶抑制劑治療反應率的預測因子。

關鍵字

肺腺癌 ； 上皮鈣黏蛋白 ； CDH1基因 ； 內皮一氧化氮合成酶基因、多型性、基因變異、表皮生長因子受體

並列摘要

EGFR mutation of non-small cell lung cancers (NSCLC) was predominantly seen in Asian population and it was considered as a predictor of therapy responsiveness. There were some known genetic polymorphisms involving the process of carcinogenesis, such as E-cadherin gene (CDH1) and endothelial nitric oxide synthase (eNOS) gene. E-cadherin is regarded as an important factor for epithelial-mesenchymal transition (EMT), which is the critical step for cancer metastasis. EMT is associated with the mutant status of EGFR and the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in lung cancer cell lines. eNOS plays a vital role in chronic inflammation and carcinogenesis. In this study, we aimed to explore their respective associations of aforementioned 2 genetic polymorphisms to EGFR mutation in patients with lung adenocarcinoma, as well as their clinical implications. A total of 280 patients with lung adenocarcinoma were recruited between years 2012 and 2015. All subjects underwent the analyses of CDH1 genetic variants (rs16260 and rs9929218) and eNOS genetic variants (-786 T/C and 894 G/T) by real-time polymerase chain reaction (PCR) genotyping. In the aspect of E-cadherin gene, the results showed that CA and CA + AA genotypes of CDH1 single nucleotide polymorphism (SNP) rs16260 were significantly reverse associated with EGFR mutation type (Adjusted odds ratio (AOR) = 0.43, 95% CI = 0.20-0.92 and AOR = 0.46, 95% CI = 0.22-0.96, respectively) in female lung adenocarcinoma patients. With regard to eNOS gene polymorphism, its variant types (GT + TT) were significantly positively correlated with EGFR mutation type, specifically exon 19 in-frame deletion. With the subgroup of EGFR L858R mutation, variant genotypes (GT + TT) of eNOS 894 G/T were significantly associated with lymph node invasion. In conclusion, our study showed that the variant types of CDH1 rs16260 and eNOS 894 G/T polymorphisms were significantly associated with EGFR mutation types of lung adenocarcinoma. With the knowledge of our findings, these genetic markers may be utilized as predictions of tumor invasiveness and EGFR-TKIs therapy responsiveness.

並列關鍵字

adenocarcinoma ； E-cadherin ； CDH1 gene ； endothelial nitric oxide synthase (eNOS) gene ； polymorphism ； genetic variants ； epidermal growth factor receptor

參考文獻

參考文獻

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