Crespo Ines, Vital Ana Louisa, Gonzalez-Tablas María, Patino María del Carmen, Otero Alvaro, Lopes María Celeste, de Oliveira Catarina, Domingues Patricia, Orfao Alberto, Tabernero Maria Dolores
Centre for Neurosciences and Cell Biology, Faculties of Pharmacy and Medicine, University of Coimbra, Coimbra, Portugal.
Department of Medicine, Centre for Cancer Research (Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer; Centro Superior de Investigaciones Científicas/Universidad de Salamanca; Instituto de Investigación Biomédica de Salamanca), University of Salamanca, Salamanca, Spain.
Am J Pathol. 2015 Jul;185(7):1820-33. doi: 10.1016/j.ajpath.2015.02.023. Epub 2015 May 11.
In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.
近年来，在多形性胶质母细胞瘤（GBM）分子生物学的理解方面取得了重要进展；因此，已经确定了复杂的基因改变和基因组图谱，这些改变和图谱经常涉及多个信号通路，从而产生了该疾病的首个分子/基因分类。在这方面，不同的基因改变和基因通路似乎可以区分原发性（例如，表皮生长因子受体（EGFR）扩增）与继发性（例如，异柠檬酸脱氢酶1/2（IDH1/2）或肿瘤蛋白p53（TP53）突变）GBM。这些基因改变针对生长因子受体-鼠肉瘤病毒癌基因同源物（RAS）信号通路，以及磷脂酰肌醇3-激酶/张力蛋白同源物（PTEN）/蛋白激酶B（AKT）、视网膜母细胞瘤/细胞周期蛋白依赖性激酶（CDK）N2A-p16（INK4A）和TP53/小鼠双微体（MDM）2/MDM4/CDKN2A-p14（ARF）通路的不同组合，这些细胞呈现出与正常神经发生关键阶段和（正常）中枢神经系统细胞类型相关的特征。这转化为明确的基因组图谱，最近癌症基因组图谱联盟已将其分为四种亚型：经典型、间充质型、原神经型和神经型GBM。在此，我们综述原发性与继发性GBM最相关的基因改变、所涉及的特定信号通路，以及这一具有遗传异质性的恶性肿瘤群体的整体基因组图谱。
