The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06030, USA.
Department of Pathology, VU University Medical Center/Brain Tumor Center Amsterdam, Amsterdam, The Netherlands.
Acta Neuropathol. 2018 May;135(5):649-670. doi: 10.1007/s00401-018-1842-y. Epub 2018 Apr 3.
At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; (II) oncogene-induced senescence; (III) stressed growth; (IV) replicative senescence/crisis; (V) immortal growth. We have integrated the findings from a large number of studies in biology and (neuro)oncology and relate somatic alterations and other results discussed in these papers to each of these five phases. Understanding the story that each glioma tells at presentation may ultimately facilitate the design of novel, more effective therapeutic approaches.
在临床表现时，成人和儿童神经胶质瘤的异质性群体携带广泛的不同体细胞基因组改变，范围从体细胞单核苷酸变异到结构性染色体重排。体细胞异常可能具有功能后果，例如 mRNA 转录本的减少、增加或改变，并且细胞会为维持这些异常付出代价。因此，这些异常必须为细胞提供竞争优势，才能成为胶质瘤基因组的一部分。在这里，我们提出了一个胶质瘤发生模型，该模型由胶质瘤细胞在临床表现前经历的以下五个连续阶段组成：（I）初始生长；（II）癌基因诱导的衰老；（III）应激生长；（IV）复制性衰老/危机；（V）永生化生长。我们整合了大量生物学和（神经）肿瘤学研究的发现，并将体细胞改变和这些论文中讨论的其他结果与这五个阶段中的每一个联系起来。了解每个呈现的胶质瘤所讲述的故事，最终可能有助于设计新的、更有效的治疗方法。
