2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/655058摘要：食道癌在台灣男性癌症死因中已躍升為第五位，在全球亦是重要癌症死因。食道癌預後極不佳，因此尋找預後相關之生物因子至為重要。核酸切除修復機制的作用已知與癌症病患的預後有關。我們先前的回溯性研究結果證實四個參與在修復機制中的單核苷酸基因多型性包括ERCC2 _R156R、ERCC4 _rs3136038、XPA _A23G及XPC_ K939Q與食道癌病患的預後相關。其中XPC_K939Q更具有預測新輔助放射與化學治療(CCRT)反應的能力。在未來三年中，我們欲針對這四個生物因子預測能力之前瞻性確認(prospective validation)與作用機制進行以下探討。臨床確認1) 利用新收集的250例食道癌病患，評估ERCC2 _R156R、ERCC4 _rs3136038、XPA_A23G、及XPC_ K939Q對食道癌預後的預測效力。2) 針對有接受CCRT的病患再進一步評估XPC_ K939Q對CCRT反應程度的預測效力。作用機制1) 探討XPC_K939Q基因型對DNA修復能力，蛋白表現位置與治療反應的關係。2) 研究ERCC2_R156R與 XPA_A23G基因型是否會影響RNA穩定性與蛋白轉譯的效率。3) 分析ERCC4_rs3136038與XPA_A23G基因型是否會影響啟動子的活性結合前瞻性臨床確認與機制研究，關於核酸切除修復機制中的生物標誌與食道癌預後的探討將更顯完備。本計畫的研究成果，將會提供珍貴的臨床應用訊息，讓食道癌病患可以根據基因背景的評估，得到更適切的治療。<br> Abstract: Esophageal cancer is among one of the major cause of cancer death worldwide. In Taiwan,esophageal cancer rises to the 5th leading cancer cause of death among the male populationThe prognosis for esophageal cancer is relatively poor with a 5-year survival rate rangingfrom around 15 to 26 % in patients undergoing various treatment modalities. An easilyassessed and reliable prognostic marker such as related single nucleotide polymorphisms(SNPs) is therefore beneficial for a more proper management of the patients with esophagealcancer. Nucleotide excision repair (NER) is known to have great impact on the survival ofcancer patients. In our retrospective study, we have demonstrated the germline SNPs of NERgenes including XPA _A23G, XPC_K939Q, ERCC2_R156R, and ERCC4_ rs3136038 haveevident association with the prognosis of the patients with esophageal cancer. One of theseSNPs, XPC_K939Q, also significantly related with the response to CCRT. In current project,we intend to perform a prospective study to validate the predictive power of these indentifiedNER biomarkers. Meanwhile, we will investigate the roles and the underlying mechanisms ofthe candidate biomarkers in the prognosis of esophageal cancer. The specific aims of theprojects in the three years to come include the approaches for clinical validation andunderlying mechanism analysis:Clinical validation:1) To evaluate the effectiveness of these 4 NER biomarkers, ERCC2_R156R, ERCC4_rs3136038, XPA_A23G, and XPC_K939Q, for predicting the clinical outcome by 250enrolled patients with esophageal cancer2) To validate the predictive power of XPC_K939Q in predicting CCRT response by theenrolled esophageal cancer patients receiving CCRT.Basic mechanism analysis:1) To explore the association of the XPC_K939Q genotypes with the DNA repair capacity,protein localization or therapy responses.2) To demonstrate whether ERCC2_R156R and XPA_A23G polymorphisms effect on themRNA stability and translation efficiency.3) To analyze the promoter activities of different ERCC4_rs3136038 and XPA_A23Ggenetic variants.Combining the the prospective validation and basic mechanism approaches, the study ofthe NER biomarkers for esophageal cancer will be more completed. We believe the findingsfrom the research will provide valuable clinical application for improving the clinicaloutcome of esophageal cancer.食道癌核酸切除修復切除修復交叉互補基因基因多型性生物標誌Esophageal cancerNucleotide Excision RepairCCRTERCC2ERCC4XPAXPCSingle Nucleotide Polymorphism (SNP)biomarker