人脑胶质瘤中IDH1基因突变与mTOR表达与患者预后的相关性研究

发布时间：2018-05-15 12:10

本文选题：胶质瘤 + IDH1基因突变　；参考：《安徽医科大学》2017年硕士论文

【摘要】：研究背景与目的:胶质瘤作为颅内最常见的恶性肿瘤,约占全部原发中枢神经系统肿瘤的70%。近年来随着显微外科技术及多种治疗模式的不断发展,越来越多的胶质瘤患者得到了及时有效的救治,但大多数患者的预后仍然不十分理想。目前关于胶质瘤的发生机制及对于其预后的判断仍有许多难以解答的疑问,在不同的胶质瘤中寻找差异基因,是目前从分子水平研究胶质瘤发展的方向。2008年Parsons在对22例胶质母细胞瘤进行基因组分析时发现:IDH1基因突变在年龄较小患者及胶质母细胞瘤发生率较高,且与患者总体存活率的增加有关,提示IDH1基因突变在人脑胶质瘤中的发生发展具有重要意义。后续的研究也表明,IDH1基因突变在II-Ⅲ级胶质瘤中的发生率约60-90%,说明IDH1基因突变在人脑中具有普遍性。最近的研究表明,发生IDH1基因突变的患者预后要好于未突变的患者。但是,有部分患者虽然发生了IDH1基因突变,生存期却相对较短,一部分患者未发生IDH1基因突变,生存期却相对较长,说明单纯靠IDH1基因突变评估患者预后存在一定的缺陷。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR),是一种非典型的丝氨酸/苏氨酸蛋白激酶,也是一种重要的信号通路转导分子,可以参与多种病理和生理过程,在基因表达和细胞增殖中发挥着桥梁作用。但胶质瘤的发生发展包含多个因素,单纯靠m TOR表达对胶质瘤进行评估亦有一定的片面性。因此,在本研究中我们尝试通过通过分析胶质瘤中IDH1基因突变及m TOR表达情况,联合评估胶质瘤患者的预后,希望能为胶质瘤患者的预后评价提供一种新的思路及方法。鉴于以上背景,本研究通过检测45例新诊断的胶质瘤患者的IDH1基因突变及m TOR表达情况,分析胶质瘤中IDH1基因突变与m TOR表达的相关性,进行差异性和相关性统计分析,进而研究其对胶质瘤病人临床治疗意义及预后判断的价值。方法:收集中国人民武装警察部队总医院神经外科2013年1月至2016年6月间经手术治疗的颅内胶质瘤病例45例,其中男性24例,女性21例,年龄8-68岁,平均42.7岁,按WHO规定将年龄段划分为两组,较年轻组(年龄≤50岁)、年龄较大组(年龄50岁)。按照WHO 2007年中枢神经系统肿瘤分类,Ⅰ级胶质瘤有2例,II级胶质瘤有26例:Ⅲ级胶质瘤9例,IV级胶质瘤8例。按病理类型的组织来源分类:来源于星形细胞的毛细胞型星形细胞瘤2例,星形细胞瘤15例,少突星形细胞瘤6例:来源于少突胶质细胞的少突胶质细胞瘤5例,间变形少突胶质细胞瘤9例:原发性胶质母细胞瘤3例,继发性胶质母细胞瘤5例。以上标本均经过本院病理科证实,病历资料完整。本组所有病理标本均在手术切除后立即于10%的福尔马林内固定保存。采用实时荧光定量PCR技术检测IDH1基因突变情况,懫用半定量兔疫组化(Envision)法检测m TOR表达情况,实验数据用SPSS20.0软件进行统计学分析。采用卡方检验,分析与不同年龄、性别、病理分级的IDH1基因突变和m TOR表达有无相关性,Spearman秩相关分析IDH1基因突变与m TOR表达相关性。中位生存时间及生存率采用Kaplan-Meier法,各组间均绘制相应生存曲线图,并采用log-rank方法分析。P0.05为差异有统计学意义。结果:1.45例脑胶质瘤患者中IDHl突变阳性者21例,其总体阳性表46.7%,在不同年龄段的差异无统计学意义(P0.05),在不同病理级别的差异无统计学意义(P0.05),在不同性别(P0.05)的差异无统计学意义。IDHl突变组中位PFS为17.6个月,野生组为14.4个月(P0.05),差异有统计学意义;IDHl突变组中位OS时间为18.2个月,野生组为15.4个月(P0.05),差异有统计学意义。2.45例胶质瘤患者中m TOR表达26例,总体阳性表达率57.8%,在不同年龄段的差异无统计学意义(P0.05);在不同病理级别的差异无统计学意义(P0.05),但病理级别增高,阳性表达率有增高趋势;在不同性别(P0.05)的差异无统计学意义。m TOR阳性表达组中位FPS为14.3个月,阴性组为17.7个月(P0.05),差异有统计学意义;m TOR阳性表达组中位OS为15.4个月,阴性组为18.8个月(P0.05),差异有统计学意义。3.本组中将45例病例分为4组,m TOR表达且IDH1基因突变的有9例(编为组1),m TOR表达而IDH1未突变的有17例(编为组2),m TOR未表达而IDH1基因突变的有15例(编为组3),m TOR未表达且IDH1基因未突变的有4例(编为组4),四组间差异有统计学意义(P0.05)。四组间分别进行生存比较,结果显示,组3与组1经统计学分析两者差异有统计学意义(P=0.024),组3与组2经统计学分析两者差异有统计学意义(P=0.048),组3与组4经统计学分析两者差异有统计学意义(P=0.008),组1与组2经统计学分析两者差异有统计学意义(P=0.043),组1与组4经统计学分析两者差异无统计学意义(P=0.237),组2与组4经统计学分析两者差异无统计学意义(P=0.631)。IHD1基因突变与m TOR表达之间存在统计学相关(P0.05)。结论:1.胶质瘤组织IDH1基因突变与患者生存期存在显著相关性,IDHl突变阳性者中位生存期明显长于阴性者,与患者年龄有相关性,与性别、病理分级无相关性。2.胶质瘤组织m TOR表达与患者生存期存在显著相关性,m TOR阳性表达者生存期明显短于阴性表达者,与患者年龄、性别、病理分级无相关性,但病理分级增高,阳性率有增高趋势。3.IHD1基因突变与m TOR表达之间存在统计学相关性,m TOR未表达而IDH1基因突变的患者预后明显好于其他患者,m TOR未表达且IDH1基因突变的患者预后好于m TOR表达而IDH1未突变的患者,m TOR表达与IDH1基因突变均可以作为胶质瘤患者预后生存指标。
[Abstract]:Background and objective: glioma is the most common malignant tumor of the brain, which accounts for the 70%. of all primary central nervous system tumors in recent years. With the development of microsurgical techniques and various treatment modes, more and more patients with glioma have been treated in time and effectively, but the prognosis of most patients is still not very ideal. At present, there are many unanswered questions about the mechanism and prognosis of glioma. Finding differential genes in different gliomas is the current direction of the development of glioma at the molecular level.2008 Parsons in the analysis of 22 cases of glioblastoma: IDH1 gene mutation at age The incidence of small patients and glioblastoma is high and is related to the increase of overall survival rate. It is suggested that the mutation of IDH1 gene in human glioma is of great significance. Subsequent studies also show that the occurrence rate of IDH1 gene mutation in II- grade III glioma is about 60-90%, indicating that the mutation of IDH1 gene is common in human brain. Recent studies have shown that the prognosis of the IDH1 gene mutation is better than that of the non mutant. However, although some patients have the IDH1 mutation, the survival time is relatively short, some patients have no IDH1 mutation and the survival time is relatively long, indicating that the prognosis of the patients only depends on the mutation of the IDH1 gene. Mammalian target of rapamycin (m TOR), an atypical serine / threonine protein kinase, is an important signaling pathway molecule, which can participate in a variety of pathological and physiological processes, play a bridge role in gene expression and cell proliferation, but the occurrence and development of glioma. There are a number of factors, and the evaluation of glioma by M TOR expression is also one-sided. Therefore, in this study, we try to evaluate the prognosis of glioma patients by analyzing the mutation of IDH1 gene and the expression of M TOR in glioma, and hope to provide a new way of thinking for the prognosis evaluation of glioma patients. Methods. In view of the above background, by detecting the IDH1 gene mutation and the expression of M TOR in 45 newly diagnosed patients with glioma, the correlation between the IDH1 gene mutation and m TOR expression in glioma was analyzed, and the difference and correlation statistical analysis were carried out, and then the value of the clinical significance and prognosis of glioma patients was studied. Methods: 45 cases of intracranial glioma in the Department of Neurosurgery of the Chinese people's Armed Police Force General Hospital from January 2013 to June 2016 were collected, including 24 males and 21 females, with an average age of 8-68 years and 42.7 years old. According to the WHO regulations, the age segment was divided into two groups, the younger group (age < 50) and the older group (age 50 years). According to the age group, the age group was 50 years old. In 2007, there were 2 cases of central nervous system tumor, grade I glioma in 2 cases, grade II glioma in 26 cases, grade III glioma in 9 cases, and grade IV glioma in 8. 2 cases of hair cell astrocytoma from astrocytes, 15 cases of astrocytoma, 6 cases of oligodendrocytoma derived from oligodendroglia. 5 cases of glioblastoma, 9 cases of deformable oligodendroglioma, 3 cases of primary glioblastoma and 5 cases of secondary glioblastoma, all of the above specimens were confirmed by the pathology department of our hospital. All the pathological specimens of this group were fixed in 10% of forminlin immediately after surgical excision. Real time fluorescence quantitative PCR was used. The IDH1 gene mutation was detected by means of semi quantitative rabbit pestilence (Envision) method. The experimental data were analyzed by SPSS20.0 software. The chi square test was used to analyze the correlation between the IDH1 gene mutation and the m TOR table with different ages, sex and pathological grades, and the Spearman rank correlation analysis of the IDH1 gene mutation. The correlation with m TOR expression. The median survival time and survival rate were Kaplan-Meier method. The corresponding survival curves were drawn between each group, and the difference of.P0.05 was statistically significant. Results: there were 21 cases of IDHl mutation positive in 1.45 patients with glioma, the positive table 46.7% of the total body was 46.7%, and there was no statistical difference between the different age groups. There was no statistical significance (P0.05) in different pathological grades (P0.05). There was no statistical significance in the difference of sex (P0.05) in the middle PFS of the.IDHl mutation group for 17.6 months, the wild group was 14.4 months (P0.05), the difference was statistically significant; the median OS time of the IDHl mutation group was 18.2 months, the wild group was 15.4 months (P0.05), and the difference was unified. There were 26 cases of M TOR expression in.2.45 patients with glioma, the overall positive expression rate was 57.8%, there was no statistical significance in different age groups (P0.05); there was no statistical significance (P0.05) at different pathological grades (P0.05), but the pathological grade increased, the positive expression rate increased, and there was no statistical significance of.M TOR in different sex (P0.05). The median FPS in the positive expression group was 14.3 months, and the negative group was 17.7 months (P0.05), the difference was statistically significant. The median OS of the m TOR positive group was 15.4 months and the negative group was 18.8 months (P0.05). The difference was statistically significant in the.3. group, the 45 cases were divided into 4 groups, m TOR table and IDH1 gene mutation were 9 cases (1), m TOR was expressed. There were 17 cases of non mutation (group 2), m TOR was not expressed while 15 cases of IDH1 gene mutation (Group 3), m TOR was not expressed and IDH1 gene was not mutated in 4 cases (Group 4). The difference between the four groups was statistically significant (P0.05). The survival comparison between the four groups was carried out respectively. The results showed that there was statistical significance between group 3 and group 1 by statistical analysis (P=). 0.024), group 3 and group 2 were statistically significant (P=0.048). Group 3 and group 4 were statistically significant (P=0.008). Group 1 and group 2 were statistically significant (P=0.043). Group 1 and group 4 were statistically significant (P=0.237), group 2 and group 4. There was no statistically significant difference between the two differences (P=0.631).IHD1 gene mutation and m TOR expression (P0.05). Conclusion: there is a significant correlation between the IDH1 gene mutation in 1. glioma tissues and the survival period of the patients. The median survival time of the IDHl mutation positive is significantly longer than the negative one, and the age has a correlation with the patient, and the sex and disease. There was a significant correlation between the expression of M TOR in.2. glioma tissue and the survival period of patients with no correlation. The survival time of M TOR positive expression was significantly shorter than that of the negative expression, and there was no correlation with age, sex and pathological grade of the patients, but the pathological grade was higher, the positive rate was higher than that of the.3.IHD1 gene mutation and the m TOR expression. The prognosis of the patients with m TOR is not expressed but the prognosis of IDH1 gene mutation is better than that of other patients. M TOR is not expressed and the prognosis of IDH1 gene mutation is better than that of M TOR expression and IDH1 non mutation. M TOR expression and IDH1 gene mutation can be used as prognostic survival index for patients with glioma.

【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R739.41

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