1] Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. [2] Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Nat Genet. 2015 May;47(5):458-68. doi: 10.1038/ng.3273. Epub 2015 Apr 13.
Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.
二级和三级胶质瘤通常是进展缓慢的脑癌，其中许多最终会转化为更具侵袭性的肿瘤。尽管最近发现 IDH1 和其他基因经常发生突变，但对其发病机制的了解仍不完整。在这里，我们结合了两组高通量测序数据，描绘了这些胶质瘤类型中遗传改变和受影响途径的全貌，敏感地检测到了驱动基因。二级和三级胶质瘤包括三个不同的亚型，其特征是存在离散的突变集和不同的临床行为。突变显示出显著的正相关和负相关以及时间层次结构，这是从共存突变中不同等位基因负担推断出来的，表明驱动克隆选择的突变之间存在功能相互作用。广泛的连续和多区域采样分析进一步支持了这一发现，并确定了在肿瘤扩张和复发过程中产生的高度时空异质性，这可能是由多个克隆选择和进化事件的复杂但有序过程塑造的。
