本文選題：膠質(zhì)瘤 + IDH1基因突變��； 參考：《安徽醫(yī)科大學(xué)》2017年碩士論文

【摘要】：研究背景與目的:膠質(zhì)瘤作為顱內(nèi)最常見的惡性腫瘤,約占全部原發(fā)中樞神經(jīng)系統(tǒng)腫瘤的70%。近年來隨著顯微外科技術(shù)及多種治療模式的不斷發(fā)展,越來越多的膠質(zhì)瘤患者得到了及時(shí)有效的救治,但大多數(shù)患者的預(yù)后仍然不十分理想。目前關(guān)于膠質(zhì)瘤的發(fā)生機(jī)制及對(duì)于其預(yù)后的判斷仍有許多難以解答的疑問,在不同的膠質(zhì)瘤中尋找差異基因,是目前從分子水平研究膠質(zhì)瘤發(fā)展的方向。2008年P(guān)arsons在對(duì)22例膠質(zhì)母細(xì)胞瘤進(jìn)行基因組分析時(shí)發(fā)現(xiàn):IDH1基因突變?cè)谀挲g較小患者及膠質(zhì)母細(xì)胞瘤發(fā)生率較高,且與患者總體存活率的增加有關(guān),提示IDH1基因突變?cè)谌四X膠質(zhì)瘤中的發(fā)生發(fā)展具有重要意義。后續(xù)的研究也表明,IDH1基因突變?cè)贗I-Ⅲ級(jí)膠質(zhì)瘤中的發(fā)生率約60-90%,說明IDH1基因突變?cè)谌四X中具有普遍性。最近的研究表明,發(fā)生IDH1基因突變的患者預(yù)后要好于未突變的患者。但是,有部分患者雖然發(fā)生了IDH1基因突變,生存期卻相對(duì)較短,一部分患者未發(fā)生IDH1基因突變,生存期卻相對(duì)較長,說明單純靠IDH1基因突變?cè)u(píng)估患者預(yù)后存在一定的缺陷。哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR),是一種非典型的絲氨酸/蘇氨酸蛋白激酶,也是一種重要的信號(hào)通路轉(zhuǎn)導(dǎo)分子,可以參與多種病理和生理過程,在基因表達(dá)和細(xì)胞增殖中發(fā)揮著橋梁作用。但膠質(zhì)瘤的發(fā)生發(fā)展包含多個(gè)因素,單純靠m TOR表達(dá)對(duì)膠質(zhì)瘤進(jìn)行評(píng)估亦有一定的片面性。因此,在本研究中我們嘗試通過通過分析膠質(zhì)瘤中IDH1基因突變及m TOR表達(dá)情況,聯(lián)合評(píng)估膠質(zhì)瘤患者的預(yù)后,希望能為膠質(zhì)瘤患者的預(yù)后評(píng)價(jià)提供一種新的思路及方法。鑒于以上背景,本研究通過檢測(cè)45例新診斷的膠質(zhì)瘤患者的IDH1基因突變及m TOR表達(dá)情況,分析膠質(zhì)瘤中IDH1基因突變與m TOR表達(dá)的相關(guān)性,進(jìn)行差異性和相關(guān)性統(tǒng)計(jì)分析,進(jìn)而研究其對(duì)膠質(zhì)瘤病人臨床治療意義及預(yù)后判斷的價(jià)值。方法:收集中國人民武裝警察部隊(duì)總醫(yī)院神經(jīng)外科2013年1月至2016年6月間經(jīng)手術(shù)治療的顱內(nèi)膠質(zhì)瘤病例45例,其中男性24例,女性21例,年齡8-68歲,平均42.7歲,按WHO規(guī)定將年齡段劃分為兩組,較年輕組(年齡≤50歲)、年齡較大組(年齡50歲)。按照WHO 2007年中樞神經(jīng)系統(tǒng)腫瘤分類,Ⅰ級(jí)膠質(zhì)瘤有2例,II級(jí)膠質(zhì)瘤有26例:Ⅲ級(jí)膠質(zhì)瘤9例,IV級(jí)膠質(zhì)瘤8例。按病理類型的組織來源分類:來源于星形細(xì)胞的毛細(xì)胞型星形細(xì)胞瘤2例,星形細(xì)胞瘤15例,少突星形細(xì)胞瘤6例:來源于少突膠質(zhì)細(xì)胞的少突膠質(zhì)細(xì)胞瘤5例,間變形少突膠質(zhì)細(xì)胞瘤9例:原發(fā)性膠質(zhì)母細(xì)胞瘤3例,繼發(fā)性膠質(zhì)母細(xì)胞瘤5例。以上標(biāo)本均經(jīng)過本院病理科證實(shí),病歷資料完整。本組所有病理標(biāo)本均在手術(shù)切除后立即于10%的福爾馬林內(nèi)固定保存。采用實(shí)時(shí)熒光定量PCR技術(shù)檢測(cè)IDH1基因突變情況,懫用半定量兔疫組化(Envision)法檢測(cè)m TOR表達(dá)情況,實(shí)驗(yàn)數(shù)據(jù)用SPSS20.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。采用卡方檢驗(yàn),分析與不同年齡、性別、病理分級(jí)的IDH1基因突變和m TOR表達(dá)有無相關(guān)性,Spearman秩相關(guān)分析IDH1基因突變與m TOR表達(dá)相關(guān)性。中位生存時(shí)間及生存率采用Kaplan-Meier法,各組間均繪制相應(yīng)生存曲線圖,并采用log-rank方法分析。P0.05為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果:1.45例腦膠質(zhì)瘤患者中IDHl突變陽性者21例,其總體陽性表46.7%,在不同年齡段的差異無統(tǒng)計(jì)學(xué)意義(P0.05),在不同病理級(jí)別的差異無統(tǒng)計(jì)學(xué)意義(P0.05),在不同性別(P0.05)的差異無統(tǒng)計(jì)學(xué)意義。IDHl突變組中位PFS為17.6個(gè)月,野生組為14.4個(gè)月(P0.05),差異有統(tǒng)計(jì)學(xué)意義;IDHl突變組中位OS時(shí)間為18.2個(gè)月,野生組為15.4個(gè)月(P0.05),差異有統(tǒng)計(jì)學(xué)意義。2.45例膠質(zhì)瘤患者中m TOR表達(dá)26例,總體陽性表達(dá)率57.8%,在不同年齡段的差異無統(tǒng)計(jì)學(xué)意義(P0.05);在不同病理級(jí)別的差異無統(tǒng)計(jì)學(xué)意義(P0.05),但病理級(jí)別增高,陽性表達(dá)率有增高趨勢(shì);在不同性別(P0.05)的差異無統(tǒng)計(jì)學(xué)意義。m TOR陽性表達(dá)組中位FPS為14.3個(gè)月,陰性組為17.7個(gè)月(P0.05),差異有統(tǒng)計(jì)學(xué)意義;m TOR陽性表達(dá)組中位OS為15.4個(gè)月,陰性組為18.8個(gè)月(P0.05),差異有統(tǒng)計(jì)學(xué)意義。3.本組中將45例病例分為4組,m TOR表達(dá)且IDH1基因突變的有9例(編為組1),m TOR表達(dá)而IDH1未突變的有17例(編為組2),m TOR未表達(dá)而IDH1基因突變的有15例(編為組3),m TOR未表達(dá)且IDH1基因未突變的有4例(編為組4),四組間差異有統(tǒng)計(jì)學(xué)意義(P0.05)。四組間分別進(jìn)行生存比較,結(jié)果顯示,組3與組1經(jīng)統(tǒng)計(jì)學(xué)分析兩者差異有統(tǒng)計(jì)學(xué)意義(P=0.024),組3與組2經(jīng)統(tǒng)計(jì)學(xué)分析兩者差異有統(tǒng)計(jì)學(xué)意義(P=0.048),組3與組4經(jīng)統(tǒng)計(jì)學(xué)分析兩者差異有統(tǒng)計(jì)學(xué)意義(P=0.008),組1與組2經(jīng)統(tǒng)計(jì)學(xué)分析兩者差異有統(tǒng)計(jì)學(xué)意義(P=0.043),組1與組4經(jīng)統(tǒng)計(jì)學(xué)分析兩者差異無統(tǒng)計(jì)學(xué)意義(P=0.237),組2與組4經(jīng)統(tǒng)計(jì)學(xué)分析兩者差異無統(tǒng)計(jì)學(xué)意義(P=0.631)。IHD1基因突變與m TOR表達(dá)之間存在統(tǒng)計(jì)學(xué)相關(guān)(P0.05)。結(jié)論:1.膠質(zhì)瘤組織IDH1基因突變與患者生存期存在顯著相關(guān)性,IDHl突變陽性者中位生存期明顯長于陰性者,與患者年齡有相關(guān)性,與性別、病理分級(jí)無相關(guān)性。2.膠質(zhì)瘤組織m TOR表達(dá)與患者生存期存在顯著相關(guān)性,m TOR陽性表達(dá)者生存期明顯短于陰性表達(dá)者,與患者年齡、性別、病理分級(jí)無相關(guān)性,但病理分級(jí)增高,陽性率有增高趨勢(shì)。3.IHD1基因突變與m TOR表達(dá)之間存在統(tǒng)計(jì)學(xué)相關(guān)性,m TOR未表達(dá)而IDH1基因突變的患者預(yù)后明顯好于其他患者,m TOR未表達(dá)且IDH1基因突變的患者預(yù)后好于m TOR表達(dá)而IDH1未突變的患者,m TOR表達(dá)與IDH1基因突變均可以作為膠質(zhì)瘤患者預(yù)后生存指標(biāo)。
[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.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R739.41

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