Novel mutations target distinct subgroups of medulloblastoma


Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

DOI: 10.1038/nature11213

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@inproceedings{Robinson2012NovelMT, title={Novel mutations target distinct subgroups of medulloblastoma}, author={Giles Robinson and Matthew Parker and Tanya A. Kranenburg and Charles Lu and Xiang Chen and Li Ding and Timothy N. Phoenix and Erin Hedlund and Lei Wei and Xiaoyan Zhu and Nader Chalhoub and Suzanne J. Baker and Robert Huether and Richard Kriwacki and Natasha Curley and Radhika Thiruvenkatam and Jianmin Wang and Gang Wu and Michael Rusch and Xin Hong and Jared Beckford and Pankaj Gupta and Jing Ma and John Easton and Bhavin Vadodaria and Arzu Onar-Thomas and Tong Lin and Shaoyi Li and Stanley Pounds and Steven Paugh and David Zhao and Daisuke Kawauchi and Martine F. Roussel and David Finkelstein and David W. Ellison and Ching C. Lau and Eric Bouffet and Tim Hassall and Sridharan Gururangan and Richard Cohn and Robert S. Fulton and Lucinda L. Fulton and David J. Dooling and Kerri Ochoa and Amar Gajjar and Elaine R. Mardis and Richard K. Wilson and James R. Downing and Jinghui Zhang and Richard J. Gilbertson}, booktitle={Nature}, year={2012} }