脑干胶质瘤是一组高度异质性、难治性疾病，主要发生在儿童及青壮年，占儿童中枢神经系统肿瘤的20%，平均生存期9-12个月，是儿童脑肿瘤死亡的主要原因之一。由于样本稀缺，目前对该病的分子机制仍缺乏足够的认识，所以其诊断、治疗和相关研究均建立在组织病理和影像分类的基础上。未来脑干胶质瘤研究领域的突破，首先需要一个整合基因组学、表观遗传学和基因表达谱数据的分子病理分型。北京天坛医院拥有世界上最大的脑干胶质瘤临床及生物样本数据库，自2010年开始与阎海教授开展关于脑干胶质瘤基因组学的合作研究，共同发现了可作为治疗靶点的特异性PPM1D基因突变，研究成果发表在Nature Genetics 杂志上。本研究拟对120例中国人脑干胶质瘤标本进行基因组学、表观遗传学和基因表达谱分析，建立和完善脑干胶质瘤的分子分型，推动脑干胶质瘤治疗的规范化、指导靶向药物的研发、确保临床研究分组设计的科学性。

Brainstem gliomas (BSGs) is a highly heterozygous entity, which is formidable to treat and carries a poor prognosis despite treatment with irradiation and chemotherapy. BSGs arises predominately in children and young adults, comprises 20% of pediatric central nervous system tumors, and is one of the leading causes of death in children with brain tumors, with a mean overall survival of 9-12 months. There is limited knowledge regarding the genetic events driving BSGs due to the unavailability of tumor tissue for modern genomic studies. Currently, the diagnosis, management strategies and relevant clinical trials of this diseases are generally based on histopathological classification and neuroimaging. A molecular classification of BSGs, which is based on an integreated analysis of the underlying genomic, epigenetic and gene expression changes on a large scale of sample size, is badly needed for the breakthrough in treatment of this disease in future. Beijing Tiantan Hospital which is affiliated to Capital Medical University of China, has established the largest BSGs clinical-biological bank in the world, and has been collaborating with Dr. Hai Yan, professor of pathology with tenure at Duke University Medical Center, on the genomic research of BSGs since 2010. This collaboration led to the discovery of a high frequency somatic gain-of-function mutations of PPM1D in BSGs, which can serve as a potential therapeutic target in the future. The outcome has been published on Nature Genetics in June 2014. For the next stage of the collaboration, we plan to perform analysis on gene mutational status, DNA copy number change, chromosomal aberrations through a gene panel testing composed of 203 cancer-related genes, and to perform global DNA methylation and gene expression analysis on 120 chinese brainstem gliomas tissues. By doing this, we aim to establish a molecular classification frame of BSGs based on the data from Chinese patients, which will help doctors to select the most optimal treatment methods, guide the development of new target drugs and guarantee the homogeneity between groups in future clinical trials on BSGs.

项目背景：脑干胶质瘤便是完全不同于大脑半球胶质瘤的一组疾病；而且，脑干胶质瘤本身因为发病年龄和起源部位的不同在预后方面也表现出显著的差异。因此利用二代测序技术，建立脑干胶质瘤的分子分型对于脑干胶质瘤的精确诊疗具有重要的意义。主要内容：对20例脑干胶质瘤样本进行了全基因组测序、RNASeq和甲基化测序。根据全基因组测序结果以及前期全外显子组测序结果，对另外83例脑干胶质瘤样本进行了68个重要基因的外显子测序，以及甲基化测序。并将测序结果和临床、病理、影像特点做了相关性分析。主要结果和数据：脑干胶质瘤常见的突变的基因包括H3F3A/HIST1H3B(61%) , TP53(50%) , NF1(20%), PPM1D(15%), ATRX (14%), IDH1(8%), PDGFRA(7%), FGFR1(4%)；常见的融合突变包括BRAF-KIAA1549、CTBP2-MIR3976HG、NEK4-ACER2、AFAP1-NTRK2、ZFPM2-IQSEC3、NDUFV1-GTF2IRD1、B4GALT1-GNPTAB。其中H3F3A和HIST1H3B均为K27M热点突变，IDH1均为R132位点的热点突变。H3F3A与IDH1突变互斥，TP53和PPM1D突变互斥存在，PPM1D突变仅出现在H3F3A突变的肿瘤中。ARTX突变既可以和H3F3A又可以和IDH1突变共存。与目前国外报道具有显著差异的发现是中国人脑干胶质瘤中HIST1H3B、ACVR1突变频率显著低于国外报道。此外，脑干胶质瘤中TERT启动子甲基化频率低（2%）、FUBP1仅1例，无CIC基因突变，提示脑干胶质瘤少枝胶质细胞瘤的发生率低。截止到2017年11月本组患者死亡75人，中位生存期是14.0个月（0.8-241.3月），根据脑干胶质瘤的常见基因突变可以将其分为三组：H3K27M 突变组，IDH1突变组，和H3K27M及IDH1野生组。三组生存时间具有显著差异。科学意义：2016年WHO中枢神经系统肿瘤分类中将脑干胶质瘤归为“伴有H3K27M突变的弥漫性中线胶质瘤”一类中，然而该分子亚型无法涵盖所有脑干胶质瘤。本项目覆盖了脑干胶质瘤所有发病年龄和起源部位的综合性研究，为进一步完善脑干胶质瘤的分子分型提供了依据，为将来临床试验设计及精准诊疗提供了理论基础。