- 學位論文
APC基因突變與結直腸癌臨床預後之相關性
Association of APC gene mutation with prognosis in colorectal cancer
摘要
已知 adenomatous polyposis coli (APC) 基因突變會造成 β-catenin 無法被磷酸化和降解，而進入到細胞核轉錄活化 c-myc、cyclin- D1 和 MMP-7 等基因表現而參與結直腸癌之腫瘤化，但是 APC基因突變與患者臨床預後之相關性則不清楚。尤其是結直腸癌患者之 p53 和 K-ras 基因亦經常發生突變，是否會影響APC基因突變與臨床預後之相關性，則仍須進一步之研究。因此本研究收集了195 位結直腸癌患者腫瘤組織之 DNA 以直接定序法 (Direct-sequencing) 分析 APC 基因在經常發生突變之區域 mutation cluster region (MCR)是否發生突變？結果發現在195位患者腫瘤組織之 APC 有66 位患者發生突變，其突變率為33.8%。而APC之突變型式主要以缺失突變 (deletion mutation) 為主，佔50.0%；其次為插入突變 (insertion mutation)，佔 25.7% 以及點突變 (point mutation) 有24.2%。又發現台灣患者之APC 突變位置主要發生於 codon 1554和 codon 1309。這些結果顯示台灣結直腸癌患者之APC突變的形式和位置與過去之研究結果有些不同。至於APC基因突變是否與患者之臨床預後有關？本研究以Kaplan-Meier analysis分析發現APC突變與195位患者之預後沒有相關性，但是若將患者區分為Duke早期 (A+B) 和Duke 晚期 (C+D) 兩群患者，則發現APC基因突變之Duke 晚期患者之存活率顯著低於沒有APC突變之患者，但是這現象卻無法在Duke 早期之患者中觀察到。若進一步以Cox regression多變項分析得知此臨床預後之相關性仍然存在。若與K-ras 基因突變合併則發現，K-ras 沒有發生突變同時APC發生突變之Duke 晚期之患者的臨床預後最差，顯示K-ras基因突變與否會影響APC突變與患者臨床預後之相關性。至於其分子機轉則有待進一步的釐清。
並列摘要
Involvement of APC mutation in colorectal carcinogenesis has been shown to upregulate c-myc, cyclin D1, and MMP-7 expressions mediated through altering phosphorylation and degradation of β-catenin to cause its nuclear translocation. However, the association between APC mutation and the clinical outcome in colorectal cancer patients are unclear. In the present study, 195 colorectal tumors were enrolled to examine the mutation cluster region (MCR) of APC gene mutation by diret sequencing. Our data showed that 66 of 195 (33.8%) of colorectal tumors were detected to occur APC mutations. We also observed that the predominat mutation patterns of APC gene was deletion mutation (50.0%), followed by insertion mutation (25.7%) and point mutation (24.2%). The hotspots of APC mutation in MCR were codons 1554 and 1309. These results were quite different from other previous reports. To verify whether APC mutation was associated with the clinical outcome of colorectal cancer patients, Kaplain-Meier analysis was first performed and data indicating that APC mutations in Duke C+D patients had lower survival rate than those without APC mutation, but this observation was not seen in all studied population and Duke A+B patients. Univariate and Cox regression analysis further confirmed the observation that APC mutation may act an independent prognostic factor in colorectal cancer patients. More interestingly, the prognostic significance of APC mutation was enhanced by wild-type K-ras in Duke C+D colorectal patients. The underlying molecular mechanisms should be further investigated.