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  • 學位論文

探討早期非小細胞肺癌的預後因素

Study on Prognostic Factors of Early Stage Non-small Cell Lung Cancer

指導教授 : 周明智 鄭雅文

摘要


肺癌在全世界是癌症有關造成死亡最常見原因,全世界每年有超過一百萬人死於肺癌。癌症分期是最適合而且是最廣泛可以被接受用來預測第一期到第四期非小細胞肺癌病患存活的参數。病理第一期非小細胞肺癌預後最好,但是大約有百分之三十第一期病患在五年內會再復發,5年存活率僅 57%–67%。僅是組織病理發現不足以預測疾病進行和臨床結果。非小細胞肺癌病患有許多預後評估因子被提出,包括K-ras、E-cadherin、bcl-2等。但鮮少探討針對於早期肺癌患者且實際應用於臨床的因子,且上述評估因子常具有種族間的差異。因此,本研究擬找出適合用於診斷台灣肺癌患者早期預後評估因子。 核糖核苷酸還原酶將核苷酸雙磷酸轉化為2'-去氧核苷酸雙磷酸中扮演一必要的角色。核糖核苷酸還原酶兩小次級單位hRRM2 和 p53R2和肺癌患者的化學治療效果有相關性,但 hRRM2和 p53R2的表現和早期非小細胞肺癌的臨床病理特徵的相關性則仍不清楚。此外,本研究過去的研究發現台灣肺癌患者有高比例的人類乳突病毒感染,而在頭頸癌的研究亦發現HPV感染之癌症患者具有較好的臨床預後,因此本研究擬分析p53R2, hRRM2及HPV 16/18 E6 蛋白表現與早期肺癌患者臨床預後的相關性。本研究利用組織微陣列的92例早期非小細胞肺癌標本和217例早期非小細胞肺癌標本都使用免疫組織化學,分別分析hRRM2、p53R2及HPV 16/18 E6 蛋白表現和臨床病理特徵,復發和轉移,和預後的相關性。分析發現p53R2的表現和臨床病理特徵無關;hRRM2僅和腫瘤惡性分化有正向關係 (P=0.006)。有關追蹤期間的存活情況,病人具有p53R2(+)/hRRM2(-)的結果最好 (P<0.01)。多變項分析發現p53R2(+)不僅可做為預期非小細胞肺癌存活的預後生物因子(風險指數0.232, 95% 信賴區間:0.086-0.626, P=0.004),而且可以預期無疾病存活的獨立生物因子(風險指數0.545,95% 信賴區間:0.301-0.987, P=0.045)。 而在分析217位第一期非小細胞肺癌病患人類乳突病毒16/18 E6 致癌蛋白表現。發現人類乳突病毒16 E6 致癌蛋白表現共有49例,佔22.6%,人類乳突病毒18 E6 致癌蛋白表現共有31例,佔14.3%。統計分析顯示發生人類乳突病毒16和18 E6 致癌蛋白表現,兩者皆以女性、沒抽菸和腺癌有顯著較高。人類乳突病毒16 E6 致癌蛋白在女性表現,經校正後勝算比是2.275 (95% 信賴區間 0.999-5.179),而腺癌病患是2.320 (95% 信賴區間1.029-5.232)。這些勝算比比男性病患和鱗狀細胞癌病患有顯著較高。有趣地是,我們發現17 位同時有人類乳突病毒16和18 E6 致癌蛋白表現的病患,有較高的5年累積存活率(5-year cumulative survival rate)72.2%,比154位都沒有致癌蛋白表現的病患48.3% 還高,有顯著性統計差異(P=0.055)。 根據本研究結果認為p53R2的表現不僅可做為預期非小細胞肺癌存活的預後生物因子,也可做為腫瘤復發的預測因子,而且p53R2的表現似乎比hRRM2的表現在早期肺癌的預後預測更重要。且HPV 16/18 E6也可用來做為預期非小細胞肺癌存活的預後生物因子,在病理第一期非小細胞肺癌可能在女性腺癌病患扮演一重要角色,也可能有利於存活率。 另外,p53R2,hRRM2及HPV 16/18 E6蛋白三者間的表現是否有關,則仍需進一步研究證明。

並列摘要


The aims of this study is to study the prognostic factors of resected early stage non-small cell lung (NSCLC). One is to understand the association of two small subunits of ribonucleotide reductase p53R2/hRRM2 expression and the clinicopathological characteristics of early stage NSCLC; the other is to investigate the association between expression of human papillomavirus 16/18 E6 oncoprotein and survival in patients with stage I NSCLC. Immunohistochemistry was conducted on tissue array that included 92 samples. Correlations between hRRM2 and p53R2 expression and clinicopathological factors, recurrence/metastasis, and outcomes were analyzed. Similarly, we analyzed a series of 217 patients with stage I NSCLC for the presence of HPV 16/18 E6 oncoprotein by immunohistochemistry. The analyses revealed that there was no correlation between p53R2 expression and clinicopathological factors; hRRM2 is only positively related to poor tumor differentiation (P=0.006). Regarding overall survival during the follow-up period, patients with p53R2(+)/hRRM2(-) had the best outcomes (P<0.01). Multi-variate Cox analysis revealed that p53R2 (risk 0.232, 95% CI: 0.086-0.626, P = 0.004) could not only serve as a prognostic biomarker to predict survival but also be served as an independent biomarker to predict disease-free survival (risk 0.545, 95% CI: 0.301-0.987, P=0.045) of NSCLC. Furthermore, HPV 16 E6 oncoprotein was expressed in 49(22.6%) patients and HPV 18 E6 oncoprotein was expressed in 31(14.3%) patients. Statistical analysis revealed that the prevalence of expression of both HPV 16 and HPV 18 E6 oncoproteins was significantly high in female patients, nonsmokers and patients with adenocarcinoma. The adjusted odds ratio for expression of HPV 16 E6 oncoprotein in female patients was 2.275 (95% confidence interval (CI), 0.999-5.179) and that in patients with adenocarcinoma was 2.320 (95% CI, 1.029-5.232). These ratios were significantly higher than those in male patients and patients with squamous cell carcinoma. Interestingly, we found that the 17 patients who expressed HPV 16 and HPV 18 E6 oncoprotein had a higher 5-year cumulative survival rate (72.2%) than the 154 patients who did not express both oncoproteins (48.3%); the difference was significant (p = 0.055). Therefore, we considered that the expression of p53R2 can be used not only as a biomarker for overall survival but also as an indicator for tumor recurrence. Base on our study, p53R2 expression seems more important than hRRM2 in early stage lung cancer prognosis. In addition, expression of HPV 16/18 E6 oncoprotein in stage I NSCLC may play an important role in female adenocarcinoma patients and survival benefits in patients who expressed HPV 16 and HPV 18 E6 oncoprotein.

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