6月20日，Nature雜志在線報道，通過對不同子群成神經(jīng)管細胞瘤患者的研究，科學家發(fā)現(xiàn)了成神經(jīng)管細胞瘤中一系列與表觀遺傳修飾和祖細胞發(fā)育有關(guān)的基因突變。
成神經(jīng)管細胞瘤是兒童惡性腦腫瘤，其中包括4個離散子群,。為確定突變驅(qū)動成神經(jīng)管細胞瘤，研究者對37例腫瘤患者的全基因組測序并和正常的血液基因組測序結(jié)果相匹配比較,。在上述研究中發(fā)現(xiàn)了一百三十六個在體細胞中存在突變的基因,，然后又在56例成神經(jīng)管細胞患者中對這些突變基因進行測序驗證。
結(jié)果新發(fā)現(xiàn)了41個過去未知與成神經(jīng)管細胞瘤相關(guān)的基因突變,。其中一些基因突變的靶點涉及不同的患者子群的表觀遺傳調(diào)節(jié)組成部分,，如在成神經(jīng)管細胞瘤患者子群3和4中的H3K27和H3K4三重甲基化的調(diào)節(jié)因子；成神經(jīng)管細胞瘤患者Wnt信號 - 子群中的CTNNB1相關(guān)的染色質(zhì)重構(gòu)因子等,。通過實驗誘導小鼠菱形唇祖細胞的某些基因突變,，以生成Wnt信號 - 子群的腫瘤，研究者發(fā)現(xiàn)了保持細胞系（DDX3X）的基因,，以及在腫瘤發(fā)生過程中啟動CDH1基因或與PIK3CA基因相互作用的基因突變,。
這些數(shù)據(jù)揭示了不同子群成神經(jīng)管細胞瘤患者的重要發(fā)病機理并為近一步的靶向性治療提供了重要參考。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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Novel mutations target distinct subgroups of medulloblastoma
Giles Robinson,1, 2, 3, 20 Matthew Parker,1, 4, 20 Tanya A. Kranenburg,1, 2, 20 Charles Lu,1, 5 Xiang Chen,1, 4 Li Ding,1, 5, 6 Timothy N. Phoenix,1, 2 Erin Hedlund,1, 4 Lei Wei,1, 4, 7 Xiaoyan Zhu,1, 2 Nader Chalhoub,1, 2 Suzanne J. Baker,1, 2 Robert Huether,1, 4, 8 Richard Kriwacki,1, 8 Natasha Curley,1, 2 Radhika Thiruvenkatam,1, 2 Jianmin Wang,1, 9 Gang Wu,1, 4 Michael Rusch,1, 4 Xin Hong,1, 5 Jared Becksfort,1, 9 Pankaj Gupta,1, 9 Jing Ma,1, 7 John Easton,1, 4 Bhavin Vadodaria,1, 4 Arzu Onar-Thomas,1, 10 Tong Lin,1, 10 Shaoyi Li,1, 10 Stanley Pounds,1, 10 Steven Paugh,1, 11 David Zhao,1, 9 Daisuke Kawauchi,1, 12 Martine F. Roussel,1, 12 David Finkelstein,1, 4 David W. Ellison,1, 7 Ching C. Lau,1, 13 Eric Bouffet,1, 14 Tim Hassall,1, 15 Sridharan Gururangan,1, 16 Richard Cohn,1, 17 Robert S. Fulton,1, 5, 6 Lucinda L. Fulton,1, 5, 6 David J. Dooling,1, 5, 6 Kerri Ochoa,1, 5, 6 Amar Gajjar,1, 3 Elaine R. Mardis,1, 5, 6, 18 Richard K. Wilson,1, 5, 6, 19 James R. Downing,1, 7 Jinghui Zhang1, 4 & Richard J. Gilbertson1, 2, 3 et al.
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.
