Novel mutations target distinct subgroups of medulloblastoma

被引:667
作者
Robinson, Giles [1 ,2 ,3 ]
Parker, Matthew [1 ,4 ]
Kranenburg, Tanya A. [1 ,2 ]
Lu, Charles [1 ,5 ]
Chen, Xiang [1 ,4 ]
Ding, Li [1 ,5 ,6 ]
Phoenix, Timothy N. [1 ,2 ]
Hedlund, Erin [1 ,4 ]
Wei, Lei [1 ,4 ,7 ]
Zhu, Xiaoyan [1 ,2 ]
Chalhoub, Nader [1 ,2 ]
Baker, Suzanne J. [1 ,2 ]
Huether, Robert [1 ,4 ,8 ]
Kriwacki, Richard [1 ,8 ]
Curley, Natasha [1 ,2 ]
Thiruvenkatam, Radhika [1 ,2 ]
Wang, Jianmin [1 ,9 ]
Wu, Gang [1 ,4 ]
Rusch, Michael [1 ,4 ]
Hong, Xin [1 ,5 ]
Becksfort, Jared [1 ,9 ]
Gupta, Pankaj [1 ,9 ]
Ma, Jing [1 ,7 ]
Easton, John [1 ,4 ]
Vadodaria, Bhavin [1 ,4 ]
Onar-Thomas, Arzu [1 ,10 ]
Lin, Tong [1 ,10 ]
Li, Shaoyi [1 ,10 ]
Pounds, Stanley [1 ,10 ]
Paugh, Steven [1 ,11 ]
Zhao, David [1 ,9 ]
Kawauchi, Daisuke [1 ,12 ]
Roussel, Martine F. [1 ,12 ]
Finkelstein, David [1 ,4 ]
Ellison, David W. [1 ,7 ]
Lau, Ching C. [1 ,13 ]
Bouffet, Eric [1 ,14 ]
Hassall, Tim [1 ,15 ]
Gururangan, Sridharan [1 ,16 ]
Cohn, Richard [1 ,17 ]
Fulton, Robert S. [1 ,5 ,6 ]
Fulton, Lucinda L. [1 ,5 ,6 ]
Dooling, David J. [1 ,5 ,6 ]
Ochoa, Kerri [1 ,5 ,6 ]
Gajjar, Amar [1 ,3 ]
Mardis, Elaine R. [1 ,5 ,6 ,18 ]
Wilson, Richard K. [1 ,5 ,6 ,19 ]
Downing, James R. [1 ,7 ]
Zhang, Jinghui [1 ,4 ]
Gilbertson, Richard J. [1 ,2 ,3 ]
机构
[1] Washington Univ, St Jude Childrens Res Hosp, Pediat Canc Genome Project, Memphis, TN 38105 USA
[2] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA
[3] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA
[4] St Jude Childrens Hosp, Dept Computat Biol & Bioinformat, Memphis, TN 38105 USA
[5] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA
[6] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63108 USA
[7] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA
[8] St Jude Childrens Hosp, Dept Biol Struct, Memphis, TN 38105 USA
[9] St Jude Childrens Hosp, Dept Informat Sci, Memphis, TN 38105 USA
[10] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA
[11] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA
[12] St Jude Childrens Hosp, Dept Tumour Biol & Genet, Memphis, TN 38105 USA
[13] Texas Childrens Canc & Hematol Ctr, Houston, TX 77030 USA
[14] Hosp Sick Children, Toronto, ON M5G 1X8, Canada
[15] Royal Childrens Hosp, Parkville, Vic 3052, Australia
[16] Duke Univ, Med Ctr, Durham, NC 27710 USA
[17] Univ New S Wales, Sch Womens & Childrens Hlth, Kensington, NSW 2052, Australia
[18] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63108 USA
[19] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA
基金
美国国家卫生研究院;
关键词
BOX RNA HELICASE; E-CADHERIN GENE; BETA-CATENIN; SOMATIC MUTATIONS; BREAST-CANCER; STEM-CELLS; DROSOPHILA; EZH2; TRANSACTIVATION; METHYLATION;
D O I
10.1038/nature11213
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:43 / 48
页数:6
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