Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) neoplasm in adults, and has an almost universally poor prognosis. Recently, an emphasis on genetic and epigenetic profiling has revealed a number of molecular features useful in the diagnostic and prognostic classification of GBM, advancing our understanding of the underlying features that make these tumors so aggressive and providing the rationale for the creation of better targeted therapeutics. One such method, DNA methylation profiling, has recently emerged as an important technique for the classification of CNS tumors, with diagnostic accuracy in some cases surpassing traditional methods. However, how DNA methylation profiles change with the course of the disease remains less understood. Here, we present a case of a 30-year-old male with primary IDH-mutant GBM with widespread recurrence and death two years later. Using unsupervised hierarchical clustering of methylation probes, we created a phylogenetic map to trace the tumor path as it spread from the initial biopsy site throughout the right hemisphere, across the corpus callosum to the contralateral hemisphere, and into the brainstem. We identified molecular divergence between the right and left hemisphere GBM samples marked by distinct copy number profile alterations, alterations in specific methylation sites, and regional loss of MGMT promoter methylation, providing a potential mechanism for treatment resistance in this case. In summary, this case both highlights the molecular diversity in GBM, and illustrates a novel use for methylation profiling in establishing a phylogenetic profile to allow for spatial mapping of tumor progression.

中文翻译：

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通过基于 DNA 甲基化的作图确定 IDH 突变型胶质母细胞瘤的空间进展和分子异质性

胶质母细胞瘤 (GBM) 是成人中最常见的恶性原发性中枢神经系统 (CNS) 肿瘤，预后几乎普遍较差。最近，对遗传和表观遗传分析的强调揭示了许多可用于 GBM 诊断和预后分类的分子特征，促进了我们对使这些肿瘤如此具有侵袭性的潜在特征的理解，并为创建更好的靶向治疗提供了基本原理. 一种这样的方法，即 DNA 甲基化分析，最近已成为一种重要的 CNS 肿瘤分类技术，在某些情况下其诊断准确性超过了传统方法。然而，DNA 甲基化谱如何随着疾病的进程而变化仍然鲜为人知。这里，我们介绍了一例 30 岁男性原发性 IDH 突变 GBM，两年后广泛复发和死亡。使用无监督的甲基化探针分层聚类，我们创建了一个系统发育图来追踪肿瘤从初始活检部位扩散到整个右半球、穿过胼胝体到对侧半球并进入脑干的路径。我们确定了右半球和左半球 GBM 样本之间的分子差异，这些样本以不同的拷贝数谱改变、特定甲基化位点的改变和 MGMT 启动子甲基化的区域丢失为标志，在这种情况下提供了治疗抵抗的潜在机制。总之，这个案例既突出了 GBM 中的分子多样性，