Brain tumors such as adult glioblastomas and pediatric high‐grade gliomas or medulloblastomas are among the leading causes of cancer‐related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single‐cell resolution have shed new light onto diverse tumor‐driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high‐grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage‐specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high‐grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors.

中文翻译：

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恶性脑肿瘤的发展起源和致癌途径。

成人肿瘤胶质母细胞瘤和小儿高级别神经胶质瘤或髓母细胞瘤等脑肿瘤是癌症相关死亡的主要原因，在过去的几十年中，预后较差，预后几乎没有改善。这些肿瘤是异质的，可以从多种神经细胞类型引发，从而导致治疗耐药性。这种异质性如何产生与起源的肿瘤细胞及其遗传改变有关。脑肿瘤的发生和发展概括了与正常神经发生有关的关键特征；然而，随着肿瘤细胞以不受控制的方式生长和分裂，其潜在机制非常失调。最近在单细胞分辨率下进行的全面基因组，转录组学和表观基因组学研究为各种肿瘤驱动事件，细胞异质性，和起源于不同脑肿瘤的细胞。原发性和继发性胶质母细胞瘤通过不同的遗传改变和途径发展，例如EGFR扩增和IDH1 / 2 / TP53突变。诸如组蛋白H3K27M的突变影响表观遗传修饰，定义了一组不同的儿科高级神经胶质瘤，例如弥漫性桥脑神经胶质瘤。独特的遗传，表观基因组特征和细胞异质性的鉴定导致了成人和小儿脑肿瘤亚型的新分类，从而为治疗分层提供了分子和谱系特异性弱点的见解。这篇综述讨论了我们目前对成年胶质母细胞瘤，小儿高级神经胶质瘤和髓母细胞瘤（恶性脑肿瘤的遗传异质性组）的起源，异质性，复发性遗传和表观遗传学改变，致癌驱动因素和信号通路的了解。