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. 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

Hiromichi Suzuki  1 , Kosuke Aoki  1 , Kenichi Chiba  2 , Yusuke Sato  3 , Yusuke Shiozawa  3 , Yuichi Shiraishi  2 , Teppei Shimamura  4 , Atsushi Niida  2 , Kazuya Motomura  5 , Fumiharu Ohka  6 , Takashi Yamamoto  5 , Kuniaki Tanahashi  5 , Melissa Ranjit  5 , Toshihiko Wakabayashi  5 , Tetsuichi Yoshizato  3 , Keisuke Kataoka  3 , Kenichi Yoshida  3 , Yasunobu Nagata  3 , Aiko Sato-Otsubo  3 , Hiroko Tanaka  2 , Masashi Sanada  3 , Yutaka Kondo  7 , Hideo Nakamura  8 , Masahiro Mizoguchi  9 , Tatsuya Abe  10 , Yoshihiro Muragaki  11 , Reiko Watanabe  12 , Ichiro Ito  12 , Satoru Miyano  2 , Atsushi Natsume  5 , Seishi Ogawa  3
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Mutational landscape and clonal architecture in grade II and III gliomas

Hiromichi Suzuki et al. Nat Genet. 2015 May.

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.

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