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Nat Genet. 2015 May;47(5):458-68. doi: 10.1038/ng.3273. Epub 2015 Apr 13.

Mutational landscape and clonal architecture in grade II and III gliomas.

Author information

1
1] Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. [2] Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
2
Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
3
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
4
Division of Systems Biology, Nagoya University School of Medicine, Nagoya, Japan.
5
Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
6
1] Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. [2] Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
7
Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
8
Department of Neurosurgery, Kumamoto University, Kumamoto, Japan.
9
Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
10
Department of Neurosurgery, Oita University, Oita, Japan.
11
Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
12
Division of Clinical Pathology, Shizuoka Cancer Center, Shizuoka, Japan.

Abstract

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.

PMID:
25848751
DOI:
10.1038/ng.3273
[Indexed for MEDLINE]

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