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    Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/4193


    Title: 探討 PERP (P53 Apoptosis Effector Related to PMP22) 之 rs648802 單核?酸多型性對於台灣人罹患肺癌的風險及對於肺癌預後的影響
    The effects of single nucleotide polymorphism (rs648802) in PERP (p53 apoptosis effector related to PMP22) on lung cancer risk and prognosis in Taiwanese population
    Authors: 王吉祥
    Chi-Hsiang,Wang
    Contributors: 中山醫學大學;醫學院;醫學分子毒理學研究所;蔡菁華
    Date: 2011
    Issue Date: 2011-10-25T07:25:24Z (UTC)
    Abstract: PERP (P53 Apoptosis Effect Related to PMP-22) 為穿膜四次的細胞膜蛋白，過去的研究認為PERP是P53的下游基因，它的表現與P53執行細胞凋亡的路徑有關；最近的研究發現PERP會影響P53的磷酸化進而穩定P53蛋白及位於細胞內的位置進而促進P53執行細胞凋亡的能力。本實驗室發現，A549、H1299、CL1-0 及肺癌患者組織中PERP的結構基因具有許多突變，其中又以C428G機率最高。而PEPR-C428G為NCBI的Database中編號 rs648802 (C428G) 之非同義單核?酸多型性。與PERP-428GG基因型相較，我們發現過度表現PERP-428CC基因型於CL1-5肺癌細胞株中，會使得細胞對於ROS有較高的抗性。PERP-C428G基因型的分佈尚未在台灣族群有研究報告，且PEPR基因多型性與非小細胞肺癌的預後關係尚無研究。因此，本論文以304位非小細胞肺癌患者及193位健康對照族群為樣本，研究PERP-C428G基因多型性在非小細胞肺癌與健康對照族群的差異，以及基因多型性與非小細胞肺癌患者之預後關係。利用統計學分析軟體spss 18.0的分析結果顯示:一、帶有PERP-428CG基因型相較於PERP-428CC基因型，有2.34倍的機率會得到肺癌(95% CI= 1.55 to 3.55)，而帶有PERP-428GG基因型相較於PERP-428CC基因型，則有5.38倍的機率會得到肺癌(95% CI= 2.12 to 13.65)。在不同臨床因子分層族群之分析結果顯示，帶有PERP-428CG及GG基因型同樣有較高且顯著的風險得到肺癌。二、分析患者預後與PERP-C428G基因多型性之相關性時發現，男性帶有PERP-428CC基因型患者相較於PERP-CG及GG有較佳之預後(P=0.009);相反地，女性則是帶PERP-428CG及GG基因型相較於PERP-428CC基因型有較佳之預後(P=0.030)。而在不同臨床因子分層分析下，同樣的是，男性帶有PERP-428CC者有較佳之預後，而女性則帶有PERP-428CG及GG有較佳之預後。這結果暗示PERP-428基因多型性與非小細胞肺癌患者預後相關係，在性別上有不同的差異。因此我們推測PERP-428基因多型性對於患者預後的相關性，可能受到性荷爾蒙所影響。三、 PERP-C428G基因多型性與性別之間的相關性只有在wild-type的P53病人中有顯著性，而在突變型的P53患者則沒有相關性。因此，我們認為P53為主要的因子具有影響男女性之間PERP-C428G基因多型性與患者預後的關係。總括而論，我們發現不論男性或女性帶有PERP-G allele 具有較高風險得到癌症，而在正常P53的患者中，帶有PERP-G allele的女性患者有較佳的預後，但男性患者則是帶有PERP-C allele者有較佳的預後。
    PERP (P53 Apoptosis Effect Related to PMP-22) –a tetraspan protein is primarily localized at the plasma membrane. Previous studies suggested that PERP is a downstream target of P53 and its expression is related to p53-dependent apoptosis. Recently, PERP has been shown to affect phosphorlyation of p53 that promotes P53-dependent apoptosis by stabilizing active p53 and altering its cellular localization. We identified multiple point mutations on the cDNA of PERP in A549, H1299 and CL1-0 lung cancer cell lines as well as lung cancer tissues. Among them, C428G mutation occurred most frequently. Based on NCBI database, PERP-C428G was confirmed to be a non-synonymous single nucleotide polymorphism. Compared with PERP-428GG genotype, we found that overexpression of PERP-428CC genotype increased the resistance of CL1-5 cancer cells to ROS treatment. The distribution of PERP-C428G genotype in Taiwanese population has not been reported. In addition, the association of PERP-C428G polymorphism with NSCLC risk and prognosis remain undefined. Therefore, we used 304 non-small cell lung cancer patients and 193 healthy control groups to investigate the risk of lung cancer in different PERP as well as the association of PERP-C428G polymorphism in NSCLC prognosis. Using statistical analysis software spss 18.0 for analyses we found that: (i) NSCLC patients with PERP-428CG genotype were at a significant 2.34-fold excess risk of lung cancer when compared to individuals with PERP-428CC genotype (95% CI= 1.55 to 3.55), ant that with PERP-428GG genotype were at a significant 5.38-fold excess risk of lung cancer when compared to individuals with PERP-428CC genotype (95% CI= 2.12 to 13.65). (ii) male patients with PERP-428CC genotype had significantly better prognosis as compared with PERP-CG and GG genotype (P = 0.009). On the contrary, female patients with PERP-CG and GG genotype had significantly better prognosis as compared with PERP-CC genotype (P=0.030). Under stratified analysis of different clinical factors, male with PERP-428CC genotype still had better prognosis, while female with PERP-428CG and GG genotype had better prognosis. Our studies suggest that effect of PERP-C428G polymorphism on prognosis of NSCLC patients were different between gender, and may be influenced by sex hormones. (iii) The differences of correlation between PERP-C428G polymorphism and prognosis in different gender was observed in patients with wild-type P53 (WT-P53) but not in that with mutant P53 (mt-P53). Therefore, we consider P53 is a dominance hierarchy over gender effect on correlation of PERP-C428G polymorphism and patient prognosis. In conclusion, we found that both male and female with PERP-G allele have higher risks of getting cancer. With wild-type p53, female patients carry PERP-G allele have better prognosis, but male patients are those with PERP-C allele have a better prognosis.
    URI: https://ir.csmu.edu.tw:8080/ir/handle/310902500/4193
    Appears in Collections:[醫學分子毒理學研究所] 博碩士論文

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