Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the “RTK I (PDGFRA)” group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

最近的研究表明，起源于不同大脑区域的神经胶质瘤之间的肿瘤驱动改变通常是不同的，并且强调了分析按大脑区域分层的神经胶质瘤分子特征的重要性。因此，为了阐明弥漫性小脑胶质瘤 (DCG) 的分子特征，我们对 27 例成人（大部分为胶质母细胞瘤）病例进行了分析。使用全外显子组测序、RNA 测序和 Infinium 甲基化阵列（ n = 17）进行的综合分析证明了与其他大脑区域的胶质瘤相比，它们具有独特的分子特征。发现了染色质修饰基因的频繁突变，其中值得注意的是SETD2中的截短突变 ( n = 4)，该突变导致 H3K36 三甲基化缺失，并且与H3F3A K27M 突变相互排斥 ( n = 3)，表明表观遗传失调可能导致 DCG 肿瘤发生。导致 p53 功能丧失的改变也很常见，包括TP53突变 ( n = 9)、 PPM1D突变 ( n = 2) 和新型PPM1D融合 ( n = 1)。另一方面，在脑胶质瘤中常见的突变和拷贝数变化并不常见。 DNA甲基化谱分析表明，除了具有H3F3A突变的DCG之外，所有DCG都被归类为“RTK I（PDGFRA）”组，并且这些DCG具有与PDGFRA高度相关的基因表达特征。 此外，与来自不同脑区的 315 个神经胶质瘤的数据相比，与神经胶质发育相关的转录因子基因的启动子甲基化显示出一种特征模式，可能反映了其肿瘤起源。值得注意的是， SOX10 （一种与少突胶质细胞分化和PDGFRA调节相关的关键转录因子）在 DCG 和 H3 K27M 突变的弥漫性中线胶质瘤中表达上调，表明它们在发育和生物学上的共性。相比之下，在大多数脑胶质瘤中， SOX10被启动子甲基化沉默。这些发现除了提供分子线索来识别 DCG 的区域相关细胞起源外，还可能提示根据神经胶质瘤的大脑区域进行潜在的定制靶向治疗。