Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.
Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.
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髓母细胞瘤外观测序发现亚型特异性体细胞突变。
DOI：
10.1038/nature11329
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发表时间：
2012-08-02
期刊：
影响因子：
64.8
通讯作者：
Cho, Yoon-Jae
中科院分区：
文献类型：
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作者：
Pugh, Trevor J.;Weeraratne, Shyamal Dilhan;Archer, Tenley C.;Krummel, Daniel A. Pomeranz;Auclair, Daniel;Bochicchio, James;Carneiro, Mauricio O.;Carter, Scott L.;Cibulskis, Kristian;Erlich, Rachel L.;Greulich, Heidi;Lawrence, Michael S.;Lennon, Niall J.;McKenna, Aaron;Meldrim, James;Ramos, Alex H.;Ross, Michael G.;Russ, Carsten;Shefler, Erica;Sivachenko, Andrey;Sogoloff, Brian;Stojanov, Petar;Tamayo, Pablo;Mesirov, Jill P.;Amani, Vladimir;Teider, Natalia;Sengupta, Soma;Francois, Jessica Pierre;Northcott, Paul A.;Taylor, Michael D.;Yu, Furong;Crabtree, Gerald R.;Kautzman, Amanda G.;Gabriel, Stacey B.;Getz, Gad;Jaeger, Natalie;Jones, David T. W.;Lichter, Peter;Pfister, Stefan M.;Roberts, Thomas M.;Meyerson, Matthew;Pomeroy, Scott L.;Cho, Yoon-Jae
髓母细胞瘤是儿童最常见的恶性脑肿瘤。识别和了解驱动这些肿瘤的遗传事件对于开发更有效的诊断、预后和治疗策略至关重要。最近，我们的团队和其他人基于转录和拷贝数描述了髓母细胞瘤的不同分子亚型。在这里，我们利用全外显子组杂交捕获和深度测序来鉴定92对原发髓母细胞瘤/正常对编码区的体细胞突变。总体而言，髓母细胞瘤表现出与其他儿科肿瘤一致的低突变率，每兆碱基中位数为0.35个非沉默突变。我们发现了12个突变频率具有统计学意义的基因，包括之前已知的髓母细胞瘤突变基因，如CTNNB1、PTCH1、MLL2、SMARCA4和TP53。在成神经管细胞瘤中发现，在RNA解旋酶基因DDX3X和核共抑制因子（N-CoR）复合物基因GPS2、BCOR和LDB1中发现了复发性体细胞突变，通常与CTNNB1突变同时发生。我们发现突变型DDX3X增强了TCF启动子的反激活，并与突变型而非野生型β -连环蛋白结合增强了细胞活力。总之，我们的研究揭示了Wnt、Hedgehog、组蛋白甲基转移酶和now - cor通路在成神经管细胞瘤和这种疾病的特定亚型中的改变，并指出RNA解旋酶DDX3X是成神经管细胞瘤致病性β -连环蛋白信号传导的一个组成部分。
Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.
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影响因子：
45.3
作者：
Remke, Marc;Hielscher, Thomas;Korshunov, Andrey
通讯作者：
Korshunov, Andrey
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
16.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Grossmann, Vera;Tiacci, Enrico;Falini, Brunangelo
通讯作者：
Falini, Brunangelo
DOI：
10.1126/science.1198056
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
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
通讯作者：
Velculescu VE