Dissecting the genomic complexity underlying medulloblastoma.
Dissecting the genomic complexity underlying medulloblastoma.
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DOI：
10.1038/nature11284
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发表时间：
2012-08-02
期刊：
影响因子：
64.8
通讯作者：
Lichter, Peter
中科院分区：
文献类型：
--
作者：
Jones, David T. W.;Jaeger, Natalie;Kool, Marcel;Zichner, Thomas;Hutter, Barbara;Sultan, Marc;Cho, Yoon-Jae;Pugh, Trevor J.;Hovestadt, Volker;Stuetz, Adrian M.;Rausch, Tobias;Warnatz, Hans-Joerg;Ryzhova, Marina;Bender, Sebastian;Sturm, Dominik;Pleier, Sabrina;Cin, Huriye;Pfaff, Elke;Sieber, Laura;Wittmann, Andrea;Remke, Marc;Witt, Hendrik;Hutter, Sonja;Tzaridis, Theophilos;Weischenfeldt, Joachim;Raeder, Benjamin;Avci, Meryem;Amstislavskiy, Vyacheslav;Zapatka, Marc;Weber, Ursula D.;Wang, Qi;Lasitschka, Baerbel;Bartholomae, Cynthia C.;Schmidt, Manfred;von Kalle, Christof;Ast, Volker;Lawerenz, Chris;Eils, Juergen;Kabbe, Rolf;Benes, Vladimir;van Sluis, Peter;Koster, Jan;Volckmann, Richard;Shih, David;Betts, Matthew J.;Russell, Robert B.;Coco, Simona;Tonini, Gian Paolo;Schueller, Ulrich;Hans, Volkmar;Graf, Norbert;Kim, Yoo-Jin;Monoranu, Camelia;Roggendorf, Wolfgang;Unterberg, Andreas;Herold-Mende, Christel;Milde, Till;Kulozik, Andreas E.;von Deimling, Andreas;Witt, Olaf;Maass, Eberhard;Roessler, Jochen;Ebinger, Martin;Schuhmann, Martin U.;Fruehwald, Michael C.;Hasselblatt, Martin;Jabado, Nada;Rutkowski, Stefan;von Bueren, Andre O.;Williamson, Dan;Clifford, Steven C.;McCabe, Martin G.;Collins, V. Peter;Wolf, Stephan;Wiemann, Stefan;Lehrach, Hans;Brors, Benedikt;Scheurlen, Wolfram;Felsberg, Joerg;Reifenberger, Guido;Northcott, Paul A.;Taylor, Michael D.;Meyerson, Matthew;Pomeroy, Scott L.;Yaspo, Marie-Laure;Korbel, Jan O.;Korshunov, Andrey;Eils, Roland;Pfister, Stefan M.;Lichter, Peter
髓母细胞瘤是一种侵袭性肿瘤，起源于小脑或髓质/脑干。它是儿童中最常见的恶性脑肿瘤，并表现出巨大的生物学和临床异质性。尽管最近的治疗取得了进展，但大约40%的儿童会经历肿瘤复发，30%的儿童将死于这种疾病。那些存活下来的人往往生活质量明显下降。四个肿瘤亚组具有不同的临床，生物学和遗传概况目前被区分。WNT肿瘤显示激活的无翼信号通路，在目前的治疗方案下具有良好的预后。SHH肿瘤表现为hedgehog通路激活，预后中等。第3组和第4组肿瘤的分子特征较差，也面临着最大的临床挑战。然而，导致这种区别的全部遗传事件仍不清楚。在这里，我们描述了125肿瘤正常对的综合深度测序分析。四倍体在第3组和第4组肿瘤中被确定为常见的早期事件，并且观察到患者年龄与突变率呈正相关。在已知的髓母细胞瘤相关基因（CTNNB1, PTCH1, MLL2, SMARCA4）和先前未与该肿瘤相关的基因（DDX3X, CTDNEP1, KDM6A, TBR1）中发现了一些复发性突变，通常以亚群特异性模式存在。rna测序证实了这些改变，并揭示了首个髓母细胞瘤融合基因的表达。染色质修饰因子在所有亚组中都经常发生改变。这些发现增强了我们对成神经管细胞瘤的基因组复杂性和异质性的理解，并为新疗法提供了几个潜在的靶点，特别是对第3组和第4组患者。
Medulloblastoma is an aggressively-growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and displays tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently discriminated. WNT tumours, displaying activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 & 4 tumours are molecularly less well-characterised, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs. Tetraploidy was identified as a frequent early event in Group 3 & 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA-sequencing confirmed these alterations, and revealed the expression of the first medulloblastoma fusion genes. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 & 4 patients.
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影响因子：
64.5
作者：
Rausch T;Jones DT;Zapatka M;Stütz AM;Zichner T;Weischenfeldt J;Jäger N;Remke M;Shih D;Northcott PA;Pfaff E;Tica J;Wang Q;Massimi L;Witt H;Bender S;Pleier S;Cin H;Hawkins C;Beck C;von Deimling A;Hans V;Brors B;Eils R;Scheurlen W;Blake J;Benes V;Kulozik AE;Witt O;Martin D;Zhang C;Porat R;Merino DM;Wasserman J;Jabado N;Fontebasso A;Bullinger L;Rücker FG;Döhner K;Döhner H;Koster J;Molenaar JJ;Versteeg R;Kool M;Tabori U;Malkin D;Korshunov A;Taylor MD;Lichter P;Pfister SM;Korbel JO
通讯作者：
Korbel JO
影响因子：
4.8
作者：
Han, Sungwon;Bahmanyar, Shirin;Goodman, Joel M.
通讯作者：
Goodman, Joel M.
影响因子：
16.2
作者：
Hevner, RF;Shi, LM;Rubenstein, JLR
通讯作者：
Rubenstein, JLR
影响因子：
30.8
作者：
van Haaften, Gijs;Dalgliesh, Gillian L.;Davies, Helen;Chen, Lina;Bignell, Graham;Greenman, Chris;Edkins, Sarah;Hardy, Claire;O'Meara, Sarah;Teague, Jon;Butler, Adam;Hinton, Jonathan;Latimer, Calli;Andrews, Jenny;Barthorpe, Syd;Beare, Dave;Buck, Gemma;Campbell, Peter J.;Cole, Jennifer;Forbes, Simon;Jia, Mingming;Jones, David;Kok, Chai Yin;Leroy, Catherine;Lin, Meng-Lay;McBride, David J.;Maddison, Mark;Maquire, Simon;Mclay, Kirsten;Menzies, Andrew;Mironenko, Tatiana;Mulderrig, Lee;Mudie, Laura;Pleasance, Erin;Shepherd, Rebecca;Smith, Raffaella;Stebbings, Lucy;Stephens, Philip;Tang, Gurpreet;Tarpey, Patrick S.;Turner, Rachel;Turrell, Kelly;Varian, Jennifer;West, Sofie;Widaa, Sara;Wray, Paul;Collins, V. Peter;Ichimura, Koichi;Law, Simon;Wong, John;Yuen, Siu Tsan;Leung, Suet Yi;Tonon, Giovanni;DePinho, Ronald A.;Tai, Yu-Tzu;Anderson, Kenneth C.;Kahnoski, Richard J.;Massie, Aaron;Khoo, Sok Kean;Teh, Bin Tean;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
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