ATRX基因突变与端粒ALT相关性对胶质瘤发生和发展的影响

ATRX is an important epigenetic regulator.It is confirmed that mutation in ATRX gene is related to the mechanism of Alternative lengthening telomere (ALT) in glioma, which could regulate telomere stability and the glioma development. However, the molecular mechanism and the correlation of mutation in ARTX gene and ALT in tumorigenesis, proliferation, and invasion has been rarely reported. We identified the molecular mechanism of mutation in ATRX gene in glioma by tissue , cell lines and animal model. Through immunohistochemical, quantitative PCR and FISH, we observed the expression and the correlation of ATRX with ALT in different gliomas with different proliferation and invasion. We observed the effect of the relationship of ATRX mutaion with ALT on the invasion of glioma by ATRX overexpression and RNAi in glioma cell lines.we identified the action of ATRX overexpression and RNAi on the invasion of glioma when the glioma cells with ATRX overexpression and RNAi were implanted in the mouse brain.In the present study, we will clarify the molecular mechamism of mutation in ATRX gene and could provide the rationale of gene therapy for gliomas.

ATRX（α-thalassemia mental retardation X-linked protein）是一个重要的表观调节因子。目前，在胶质瘤中发现ATRX基因突变与非端粒酶依赖的端粒延长替代机制（ALT）相关，其可能是通过影响端粒的稳定性而导致胶质瘤的发生和发展。但是，ARTX基因突变与ALT相关性对胶质瘤发生和发展的影响尚无研究报道。本研究拟探讨ATRX的分子生物学功能，通过测序比较侵袭性和非侵袭性肿瘤的ATRX基因突变情况，通过临床标本的免疫组化、FISH等方法，观察不同增殖侵袭性胶质瘤的ATRX表达及与ALT的相关性；通过qPCR等方法检测侵袭性相关分子表达，观察ATRX与ALT相关性在肿瘤细胞发生和发展中的作用机制，旨在为探索胶质瘤的发病机制和找到新的治疗靶点奠定基础

体外研究证实ATRX基因突变的胶质瘤细胞中无ATRX表达，而存在ALT表型。儿童脑干胶质瘤ATRX/H3.3蛋白复合物的基因突变占了45%，我们进一步在我们的标本中检测H3.3基因突变情况及其预后分析。脑干与丘脑胶质瘤预后不良，本研究对脑干及丘脑胶质瘤进行基因组学研究，来对临床及预后进行对比。25例脑干胶质瘤和13例丘脑胶质瘤，H3F3A，IDH1和TP53通过测序获得。 脑干及丘脑胶质瘤的分组中性别和年龄无统计学差异，丘脑胶质瘤中高级别肿瘤更多。在丘脑胶质瘤中，有K27突变的患者生存期比H3F3A野生型生存期长(p = 0.029)。然而在脑干胶质瘤中无统计学差异 (p = 0.236)。基因学分析发现，K27M突变覆盖TP53 的突变，与IDH1突变相互排斥。微阵列显示在有K27M突变的丘脑和脑干胶质瘤中存在86个差异基因表达，29个基因涉及40个通路。尽管在脑干和丘脑胶质瘤中K27M突变常见，但是仅仅在丘脑中发现K27M突变与预后好相关。丘脑胶质瘤和脑干胶质瘤具有广泛的基因差异。

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