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  • 學位論文

可手術切除的非小細胞肺癌中CIMP對其預後影響之研究

Investigation of CpG Island Methylator Phenotype (CIMP) in the Prognosis of Resectable NSCLC

指導教授 : 陳永恩
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摘要


表基因變異在肺癌的形成與惡化扮演重要的角色,到目前為止,尚未有學者針對在非小細胞肺癌中,做有關訊號傳遞路徑相關的CpG island methylator phenotype (CIMP)研究。在我們這次研究,使用methylation-specific PCR (MSP)方法,檢驗69位手術切除的肺癌組織以及69個癌症旁邊正常的組織檢體,分析有關TGF-β訊號傳遞路徑和WNT訊號傳遞路徑相關的抑癌基因異常甲基化的情形。CIMP positive代表檢體具有6個或6個以上的異常基因甲基化的情形。我們發現在所有非小細胞肺癌中,每個腫瘤檢體都至少有1個抑癌基因的啟動子有異常甲基化,而且所有腫瘤檢體的甲基化基因數目的分布,呈現統計上的雙峰分布。10個基因啟動子的甲基化頻率從DKK的17.4%到SFRP1的92.8%不等。有趣的是,在46.4% (32/69)的非小細胞肺癌中有CIMP+的情形,而在相對鄰近正常組織中有26.1% (18/69)有CIMP+的情形; 在53.6% (37/69)的非小細胞肺癌中有CIMP−的情形,而在相對鄰近正常組織中有73.9% (51/69)有CIMP−的情形。這結果顯示 CIMP 的高低狀態和腫瘤與相對鄰近正常組織有顯著的關係存在(P = 0.011)。除此之外,CIMP 的高低狀態似乎也和非小細胞肺癌的存活期有顯著的相關 (P = 0.006)。 在現今的研究中,我們是第一個探討在非小細胞肺癌中,訊號傳遞路徑相關的抑癌基因具有CIMP 的現象,同時也發現這CIMP指標也是非小細胞肺癌根除手術後,預測癌症整體存活期的獨立因子,進而能幫助臨床醫師對早期CIMP positive 的病人,在癌症的個人化治療與監控上提供更有效的參考指標。

並列摘要


Epigenetic alterations play an important role in the development and progression of lung cancer. "CpG island methylator phenotype (CIMP) involving methylation abnormalities of different signaling pathways has not been so far epigenetically elucidated in non-small cell lung cancer (NSCLC). Using methylation-specific PCR (MSP) method, we examined methylation profiles for ten tumor suppressor genes (TSGs) related to TGF-β signaling pathway and WNT signaling pathway in 69 NSCLC tissues and 69 paired adjacent normal tissues. CIMP positive (CIMP+) is referred to having six or more than six synchronously methylated genes per sample. Consequently, all NSCLC presented promoter methylation of at least one gene while the distribution of methylated gene numbers in all NSCL showed bimodal distribution. The frequency of promoter methylation for ten genes explored ranged from 17.4% for DKK to 92.8% for SFRP1. Interestingly, CIMP+ was found in 46.4% (32/69) of NSCLC and in 26.1% (18/69) of paired adjacent normal tissues; CIMP− was present in 53.6% (37/69) of NSCLC, 73.9% (51/69) of paired adjacent normal tissues. The data suggest that CIMP status was significantly associated with NSCLC and paired adjacent normal tissues (P = 0.011). In addition, there appeared to be a significant association between CIMP status and progression free survival prognosis of NSCLC (P = 0.006). In the present study, for the first time, we discovered the presence of signaling pathway associated CIMP in the resectable lung cancer and it indicated an effective independent predict factor for overall survival after curative surgery. We hope our result could supply the effective biomarker to the clinician for tailored therapy and monitor of early CIMP positive lung cancer patients.

參考文獻


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