Affymetrix SNP 6.0 array data for Diffuse Intrinsic Pontine Glioma. Homo sapiens

Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Overall design: Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from snap frozen biopsy and autopsy brain tissue from DIPG patients. Copy number analysis on Affymetrix 6.0 SNP arrays was performed for 45 paediatric DIPG samples, 27 matched normal brain samples, and HapMap samples.

弥漫内生型桥脑胶质瘤（Diffuse Intrinsic Pontine Glioma, DIPG）是一种发生于儿童脑干部的致命性脑恶性肿瘤，目前尚无有效治疗方案，死亡率接近100%。多数治疗方案失效的核心原因，在于此类肿瘤所处的位置极为敏感脆弱，且过往治疗选择均基于“DIPG在分子层面与成人脑胶质瘤相似”的假设。近年的研究已揭示了该肿瘤独特的遗传特征：近80%的病例携带K27M-H3.3或K27M-H3.1突变。然而，学界目前仍将DIPG视为单一疾病，对其肿瘤遗传驱动机制的认知仍十分有限。为阐明DIPG的致病驱动因素，本研究将全基因组测序与甲基化、转录表达及拷贝数谱分析相结合，不仅发现DIPG可分为三个分子特征迥异的亚型（H3-K27M型、沉默型、MYCN型），还在20%的DIPG病例中鉴定出激活素受体ACVR1的新型复发性激活突变。ACVR1突变可使其组成型激活，进而介导SMAD蛋白磷酸化，并促使下游激活素信号通路靶点ID1与ID2的表达水平上调。本研究结果为这款不治的儿童脑肿瘤揭示了差异化的分子亚型与全新治疗靶点。实验整体设计：按照制造商提供的操作指南，对DIPG患者的速冻活检及尸检脑组织提取的DNA进行Affymetrix SNP芯片检测。针对Affymetrix 6.0 SNP芯片的拷贝数分析共纳入45例儿童DIPG样本、27例匹配正常脑组织样本及HapMap样本。