Subgroup-specific structural variation across 1,000 medulloblastoma genomes

被引：658

作者：

Northcott, Paul A. ^{[2
,3
]}

Shih, David J. H. ^{[2
,4
]}

Peacock, John ^{[2
,4
]}

Garzia, Livia ^{[2
]}

Morrissy, A. Sorana ^{[2
]}

Zichner, Thomas ^{[5
]}

Stuetz, Adrian M. ^{[5
]}

Korshunov, Andrey ^{[6
]}

Reimand, Jueri ^{[7
]}

Schumacher, Steven E. ^{[8
]}

Beroukhim, Rameen ^{[8
,9
,10
,11
,12
,13
]}

Ellison, David W. ^{[14
]}

Marshall, Christian R. ^{[15
,16
]}

Lionel, Anath C. ^{[17
]}

Mack, Stephen ^{[2
,4
]}

Dubuc, Adrian ^{[2
,4
]}

Yao, Yuan ^{[2
,4
]}

Ramaswamy, Vijay ^{[2
,4
]}

Luu, Betty ^{[2
]}

Rolider, Adi ^{[2
]}

Cavalli, Florence M. G. ^{[2
]}

Wang, Xin ^{[2
,4
]}

Remke, Marc ^{[2
]}

Wu, Xiaochong ^{[2
]}

Chiu, Readman Y. B. ^{[18
]}

Chu, Andy ^{[18
]}

Chuah, Eric ^{[18
]}

Corbett, Richard D. ^{[18
]}

Hoad, Gemma R. ^{[18
]}

Jackman, Shaun D. ^{[18
]}

Li, Yisu ^{[18
]}

Lo, Allan ^{[18
]}

Mungall, Karen L. ^{[18
]}

Nip, Ka Ming ^{[18
]}

Qian, Jenny Q. ^{[18
]}

Raymond, Anthony G. J. ^{[18
]}

Thiessen, Nina ^{[18
]}

Varhol, Richard J. ^{[18
]}

Birol, Inanc ^{[18
]}

Moore, Richard A. ^{[18
]}

Mungall, Andrew J. ^{[18
]}

Holt, Robert ^{[1
]}

Kawauchi, Daisuke ^{[14
]}

Roussel, Martine F. ^{[14
]}

Kool, Marcel ^{[3
]}

Jones, David T. W. ^{[3
]}

Witt, Hendrick ^{[19
,20
,21
]}

Fernandez-L, Africa ^{[22
]}

Kenney, Anna M.

Wechsler-Reya, Robert J. ^{[23
]}

机构：

[1] Michael Smith Genome Sci Ctr, BC Canc Agcy, Vancouver, BC V5Z 1L3, Canada

[2] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 1L7, Canada

[3] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[4] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada

[5] European Mol Biol Lab, D-69117 Heidelberg, Germany

[6] Heidelberg Univ, German Canc Res Ctr DKFZ, Dept Neuropathol, CCU Neuropathol, D-69120 Heidelberg, Germany

[7] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[8] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[9] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[10] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[11] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[12] Broad Inst, Canc Program, Cambridge, MA 02142 USA

[13] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[14] St Jude Childrens Res Hosp, Memphis, TN 38105 USA

[15] Univ Toronto, McLaughlin Ctr, Toronto, ON M5G 1L7, Canada

[16] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada

[17] Hosp Sick Children, Ctr Appl Genom & Program Genet & Genome Biol, Toronto, ON M5G 1L7, Canada

[18] Michael Smith Genome Sci Ctr, BC Canc Agcy, Vancouver, BC V5Z 4S6, Canada

[19] Univ Heidelberg Hosp, Dept Pediat Oncol, D-69120 Heidelberg, Germany

[20] Univ Heidelberg Hosp, Dept Hematol, D-69120 Heidelberg, Germany

[21] Univ Heidelberg Hosp, Dept Immunol, D-69120 Heidelberg, Germany

[22] Mem Sloan Kettering Canc Ctr, Pediat Clin Trials Off, New York, NY 10174 USA

[23] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA

[24] Hosp Sick Children, Dept Surg, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[25] Hosp Sick Children, Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada

[26] Childrens Mem Hlth Inst, Dept Pathol, PL-04730 Warsaw, Poland

[27] Childrens Mem Hlth Inst, Dept Oncol, Warsaw, Poland

[28] Med Univ Vienna, Inst Neurol, A-1097 Vienna, Austria

[29] Inst Curie, INSERM, U830, F-75238 Paris 5, France

[30] Inst Curie, Unit Somat Genet, F-75238 Paris 5, France

[31] Inst Curie, Dept Pediat Oncol, F-75248 Paris 5, France

[32] CHUV Univ Hosp, CH-1011 Lausanne, Switzerland

[33] Seoul Natl Univ, Childrens Hosp, Dept Neurosurg, Div Pediat Neurosurg, Seoul 110744, South Korea

[34] Cnopfsche Kinderklin, D-90419 Nurnberg, Germany

[35] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[36] Johns Hopkins Univ, Sch Med, Dept Ophthalmol & Oncol, Baltimore, MD 21205 USA

[37] Univ Lyon, Ctr Rech Neurosci, CNRS UMR5292, INSERM U1028, F-69336 Lyon, France

[38] Univ Lyon, Grp Hosp EST, Ctr Pathol EST, F-69500 Bron, France

[39] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15224 USA

[40] Univ Michigan, Sch Med, Dept Neurosurg, Ann Arbor, MI 48109 USA

[41] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

[42] Univ Alabama Birmingham, Dept Surg, Div Neurosurg, Birmingham, AL 35294 USA

[43] Catholic Univ, Sch Med, I-00186 Rome, Italy

[44] Erasmus MC, Dept Pediat Oncol & Hematol, NL-3000 Rotterdam, Netherlands

[45] Erasmus MC, Dept Neurol, NL-3000 CA Rotterdam, Netherlands

[46] Erasmus MC, Dept Pathol, NL-3015 GE Rotterdam, Netherlands

[47] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[48] Seattle Childrens Hosp, Seattle, WA 98104 USA

[49] Univ Washington, Sch Med, Harborview Med Ctr, Seattle, WA 98104 USA

[50] Masaryk Univ, Sch Med, Dept Pediat Oncol, Brno 61300, Czech Republic

来源：

NATURE | 2012年 / 488卷 / 7409期

基金：

美国国家卫生研究院;

关键词：

HEDGEHOG PATHWAY INHIBITOR; COPY-NUMBER ALTERATION; ALPHA-SYNUCLEIN; BETA FAMILY; SYNPHILIN-1; PROTEIN; MYC; LANDSCAPE; MUTATION; TARGETS;

D O I：

10.1038/nature11327

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, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.

引用

页码：49 / 56

页数：8

共 40 条

[1] OTX2 Is Critical for the Maintenance and Progression of Shh-Independent Medulloblastomas [J].

Adamson, David C. ;

Shi, Qun ;

Wortham, Matthew ;

Northcott, Paul A. ;

Di, Chunhui ;

Duncan, Christopher G. ;

Li, Jianjun ;

McLendon, Roger E. ;

Bigner, Darell D. ;

Taylor, Michael D. ;

Yan, Hai .

CANCER RESEARCH, 2010, 70 (01) :181-191

[2] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[3] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[4] The TGF-β co-receptor, CD109, promotes internalization and degradation of TGF-β receptors [J].

Bizet, Albane A. ;

Liu, Kai ;

Tran-Khanh, Nicolas ;

Saksena, Anshuman ;

Vorstenbosch, Joshua ;

Finnson, Kenneth W. ;

Buschmann, Michael D. ;

Philip, Anie .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2011, 1813 (05) :742-753

[5] NFKBIA Deletion in Glioblastomas. [J].

Bredel, Markus ;

Scholtens, Denise M. ;

Yadav, Ajay K. ;

Alvarez, Angel A. ;

Renfrow, Jaclyn J. ;

Chandler, James P. ;

Yu, Irene L. Y. ;

Carro, Maria S. ;

Dai, Fangping ;

Tagge, Michael J. ;

Ferrarese, Roberto ;

Bredel, Claudia ;

Phillips, Heidi S. ;

Lukac, Paul J. ;

Robe, Pierre A. ;

Weyerbrock, Astrid ;

Vogel, Hannes ;

Dubner, Steven ;

Mobley, Bret ;

He, Xiaolin ;

Scheck, Adrienne C. ;

Sikic, Branimir I. ;

Aldape, Kenneth D. ;

Chakravarti, Arnab ;

Harsh, Griffith R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (07) :627-637

[6] Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma [J].

Buonamici, Silvia ;

Williams, Juliet ;

Morrissey, Michael ;

Wang, Anlai ;

Guo, Ribo ;

Vattay, Anthony ;

Hsiao, Kathy ;

Yuan, Jing ;

Green, John ;

Ospina, Beatriz ;

Yu, Qunyan ;

Ostrom, Lance ;

Fordjour, Paul ;

Anderson, Dustin L. ;

Monahan, John E. ;

Kelleher, Joseph F. ;

Peukert, Stefan ;

Pan, Shifeng ;

Wu, Xu ;

Maira, Sauveur-Michel ;

Garcia-Echeverria, Carlos ;

Briggs, Kimberly J. ;

Watkins, D. Neil ;

Yao, Yung-mae ;

Lengauer, Christoph ;

Warmuth, Markus ;

Sellers, William R. ;

Dorsch, Marion .

SCIENCE TRANSLATIONAL MEDICINE, 2010, 2 (51)

[7] The PVT-1 oncogene is a myc protein target is overexpressed in transformed cells [J].

Carramusa, Letizia ;

Contino, Flavia ;

Ferro, Arianna ;

Minafra, Luigi ;

Perconti, Giovanni ;

Giallongo, Agata ;

Feo, Salvatore .

JOURNAL OF CELLULAR PHYSIOLOGY, 2007, 213 (02) :511-518

[8] Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome [J].

Cho, Yoon-Jae ;

Tsherniak, Aviad ;

Tamayo, Pablo ;

Santagata, Sandro ;

Ligon, Azra ;

Greulich, Heidi ;

Berhoukim, Rameen ;

Amani, Vladimir ;

Goumnerova, Liliana ;

Eberhart, Charles G. ;

Lau, Ching C. ;

Olson, James M. ;

Gilbertson, Richard J. ;

Gajjar, Amar ;

Delattre, Olivier ;

Kool, Marcel ;

Ligon, Keith ;

Meyerson, Matthew ;

Mesirov, Jill P. ;

Pomeroy, Scott L. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (11) :1424-1430

[9] Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1:: implications for Lewy-body formation in Parkinson disease [J].

Chung, KKK ;

Zhang, Y ;

Lim, KL ;

Tanaka, Y ;

Huang, H ;

Gao, J ;

Ross, CA ;

Dawson, VL ;

Dawson, TM .

NATURE MEDICINE, 2001, 7 (10) :1144-1150

[10] Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions [J].

Engelender, S ;

Kaminsky, Z ;

Guo, X ;

Sharp, AH ;

Amaravi, RK ;

Kleiderlein, JJ ;

Margolis, RL ;

Troncoso, JC ;

Lanahan, AA ;

Worley, PF ;

Dawson, VL ;

Dawson, TM ;

Ross, CA .

NATURE GENETICS, 1999, 22 (01) :110-114

← 1 2 3 4 →