title: Mutational landscape and clonal architecture in grade II and III gliomas.
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.
authors.affiliation: 1] Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. [2] Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: 1] Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. [2] Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Division of Systems Biology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Motomura
authors.affiliation: 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.
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Ohka
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tanahashi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Melissa
authors.initials: M
authors.lastname: Ranjit
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Neurosurgery, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mizoguchi
authors.affiliation: Department of Neurosurgery, Oita University, Oita, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Muragaki
authors.affiliation: Division of Clinical Pathology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Division of Clinical Pathology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ito
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality; D056915:DNA Copy Number Variations; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics* / Q000401:mortality; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading