Department of Neurosurgery, University of Utah, Salt Lake City, UT 84132, USA.
Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA.
Front Biosci (Landmark Ed). 2014 Jun 1;19(7):1065-87. doi: 10.2741/4268.
Glioblastoma (GBM), the most common primary brain tumor, has a poor median prognosis despite modern surgical, chemotherapeutic, and radiation modalities, which have shown little clinical efficacy. Initially categorized by clinicopathological classification into de novo primary GBM and secondary GBM, which arises from lower-grade glioma, genomic studies have elucidated several distinct genotypes. In addition, distinct patterns of dysregulated epidermal growth factor receptor, platelet-derived growth factor receptor, p53, phosphatase and tensin homolog, cell cycle proteins, and isocitrate dehydrogenase 1, as well as loss of heterozygosity in multiple chromosomes complicate the GBM mutational landscape. Even with the many approaches in targeting these mutations, a long-standing clinical cure remains limited because of the tremendous heterogeneity and challenges in developing targeted treatments. Furthermore, this cancer utilizes ingenious approaches to subvert targeted agents and pathological variants of GBM demonstrate distinct molecular signatures, which may impact prognosis. This review discusses the collective understanding of GBM heterogeneity, including molecular, histopathological, and genomic features; why treatments have failed in the past; and how future clinical trials and therapies can be devised.
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，尽管采用了现代的手术、化疗和放疗方法，但预后仍然很差，这些方法的临床疗效甚微。最初根据临床病理分类，分为新诊断的原发性 GBM 和继发性 GBM，后者源于低级别胶质瘤，基因组研究已经阐明了几种不同的基因型。此外，表皮生长因子受体、血小板衍生生长因子受体、p53、磷酸酶和张力蛋白同系物、细胞周期蛋白和异柠檬酸脱氢酶 1 的失调模式以及多个染色体的杂合性丢失使 GBM 的突变景观变得复杂。即使有许多针对这些突变的方法，由于巨大的异质性和开发靶向治疗的挑战，长期的临床治愈仍然有限。此外，这种癌症采用巧妙的方法来颠覆靶向药物，而 GBM 的病理性变异则表现出不同的分子特征，这可能影响预后。这篇综述讨论了对 GBM 异质性的综合认识，包括分子、组织病理学和基因组特征；为什么过去的治疗方法失败了；以及如何设计未来的临床试验和治疗方法。
