Mutational landscape and clonal architecture in grade II and III gliomas
Mutational landscape and clonal architecture in grade II and III gliomas
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DOI：
10.1038/ng.3273
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发表时间：
2015-05-01
期刊：
影响因子：
30.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Suzuki, Hiromichi;Aoki, Kosuke;Ogawa, Seishi
II级和III级胶质瘤通常是进展缓慢的脑癌，其中许多最终转化为更具侵袭性的肿瘤。尽管最近发现IDH1和其他基因频繁突变，但对其发病机制的了解仍然不完整。在这里，结合两大组高通量测序数据，我们描绘了这些胶质瘤类型中遗传改变和受影响途径的全貌，并对驱动基因进行了灵敏的检测。II级和III级胶质瘤包括三种不同的亚型，其特征在于离散的突变集和不同的临床行为。突变表现出显着的正相关和负相关，并按时间顺序的层次结构，从不同的等位基因之间的共存突变的负担推断，这表明有驱动克隆选择的突变之间的功能相互作用。广泛的系列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期间产生的高度时空异质性，这可能是由复杂但有序的多克隆选择和进化事件过程形成的。
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.