The genetic landscape of the childhood cancer medulloblastoma.
The genetic landscape of the childhood cancer medulloblastoma.
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DOI：
10.1126/science.1198056
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发表时间：
2011-01-28
期刊：
影响因子：
--
通讯作者：
Velculescu VE
中科院分区：
文献类型：
--
作者：
Parsons DW;Li M;Zhang X;Jones S;Leary RJ;Lin JC;Boca SM;Carter H;Samayoa J;Bettegowda C;Gallia GL;Jallo GI;Binder ZA;Nikolsky Y;Hartigan J;Smith DR;Gerhard DS;Fults DW;VandenBerg S;Berger MS;Marie SK;Shinjo SM;Clara C;Phillips PC;Minturn JE;Biegel JA;Judkins AR;Resnick AC;Storm PB;Curran T;He Y;Rasheed BA;Friedman HS;Keir ST;McLendon R;Northcott PA;Taylor MD;Burger PC;Riggins GJ;Karchin R;Parmigiani G;Bigner DD;Yan H;Papadopoulos N;Vogelstein B;Kinzler KW;Velculescu VE
髓母细胞瘤是儿童最常见的恶性脑肿瘤。为了鉴定这种肿瘤类型的遗传改变，我们使用高密度微阵列搜索拷贝数改变，并使用桑格测序法在一组22 MB中对所有已知的蛋白质编码基因和miRNA基因进行测序。我们发现，平均而言，每个肿瘤有11个基因改变，比迄今为止测序的成人实体瘤少5到10倍。除了Hedgehog和Wnt通路的改变外，我们的分析还发现了以前不知道在MB中改变的基因。最值得注意的是，在16%的MB患者中发现了组蛋白-赖氨酸N-甲基转移酶基因MLL 2或MLL 3的失活突变。这些结果证明了成人和儿童癌症遗传景观之间的关键差异，突出了发育途径的失调作为MB的重要机制，并确定了特定类型的组蛋白甲基化在人类肿瘤发生中的作用。
Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, 5 to 10-fold fewer than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.
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