Comprehensive genomic characterization defines human glioblastoma genes and core pathways

被引：5966

作者：

Chin, L. ^{[1
,2
,3
]}

Meyerson, M. ^{[1
,4
]}

Aldape, K. ^{[9
]}

Bigner, D. ^{[5
]}

Mikkelsen, T. ^{[7
]}

VandenBerg, S. ^{[8
]}

Kahn, A. ^{[12
]}

Penny, R. ^{[15
]}

Ferguson, M. L. ^{[16
]}

Gerhard, D. S. ^{[14
]}

Getz, G. ^{[4
]}

Brennan, C. ^{[21
]}

Taylor, B. S. ^{[22
,23
]}

Winckler, W. ^{[1
,4
]}

Park, P. ^{[18
,19
,20
]}

Ladanyi, M. ^{[24
]}

Hoadley, K. A. ^{[34
]}

Verhaak, R. G. W. ^{[1
,4
]}

Hayes, D. N. ^{[36
]}

Spellman, Paul T. ^{[25
]}

Absher, D. ^{[52
]}

Weir, B. A. ^{[1
,4
]}

Ding, L. ^{[17
]}

Wheeler, D. ^{[31
]}

Lawrence, M. S. ^{[4
]}

Cibulskis, K. ^{[46
]}

Mardis, E. ^{[17
]}

Zhang, Jinghui ^{[56
]}

Wilson, R. K. ^{[17
]}

Donehower, L. ^{[31
]}

Wheeler, D. A. ^{[31
]}

Purdom, E. ^{[26
]}

Wallis, J. ^{[17
]}

Laird, P. W. ^{[43
]}

Herman, J. G. ^{[36
]}

Schuebel, K. E. ^{[36
]}

Weisenberger, D. J. ^{[43
]}

Baylin, S. B. ^{[36
]}

Schultz, N. ^{[22
]}

Yao, Jun ^{[2
]}

Wiedemeyer, R. ^{[1
]}

Weinstein, J. ^{[57
]}

Sander, C. ^{[22
]}

Gibbs, R. A.

Gray, J. ^{[25
]}

Kucherlapati, R. ^{[19
]}

Lander, E. S. ^{[4
,48
,49
]}

Myers, R. M. ^{[52
]}

Perou, C. M. ^{[32
,33
]}

McLendon, Roger ^{[5
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Ctr Appl Canc Sci, Belfer Inst innovat Canc Sci, Boston, MA 02115 USA

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

[4] Harvard Univ, Cambridge, MA 02142 USA

[5] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA

[6] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA

[7] Henry Ford Hosp, Dept Neurol Surg, Detroit, MI 48202 USA

[8] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[9] Univ Texas Houston MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[10] Univ Texas Houston MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA

[11] Univ Texas Houston MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA

[12] SRA Int, Fairfax, VA 22033 USA

[13] NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA

[14] NCI, NIH, Bethesda, MD 20892 USA

[15] Int Genom Consortium, Phoenix, AZ 85004 USA

[16] MLF Consulting, Arlington, MA 02474 USA

[17] Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63108 USA

[18] Harvard Univ, Sch Med, Partners Healthcare Ctr Genet & Genom, Boston, MA 02115 USA

[19] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA

[20] Childrens Hosp, Informat Program, Boston, MA 02115 USA

[21] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA

[22] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA

[23] Weill Cornell Grad Sch Med Sci, Dept Physiol & Biophys, New York, NY 10065 USA

[24] Mem Sloan Kettering Canc Ctr, Dept Pathol, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[25] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA

[26] Univ Calif Berkeley, Dept Stat, Berkeley, CA 95720 USA

[27] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 95720 USA

[28] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[29] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA

[30] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA

[31] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol Virol & Microbiol, Houston, TX 77030 USA

[32] Baylor Coll Med, Grad Program Struct & Computat Biol & Mol Biophys, Houston, TX 77030 USA

[33] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[34] Univ N Carolina, Dept Pathol & Lab Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[35] Univ N Carolina, Dept Internal Med, Lineberger Comprehens Canc Ctr, Div Med Oncol, Chapel Hill, NC 27599 USA

[36] Johns Hopkins Univ, Div Canc Biol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[37] Johns Hopkins Univ, Biometry & Clin Trials Div, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[38] Univ Ghent, Fac Biosci & Engn, Dept Mol Biotechnol, B-9000 Ghent, Belgium

[39] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA

[40] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA

[41] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA

[42] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA

[43] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90089 USA

[44] Henry Ford Hosp, Dept Pathol, Detroit, MI 48202 USA

[45] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA

[46] MIT, Eli & Edythe L Broad Inst, Canc Genome Project, Cambridge, MA 02142 USA

[47] MIT, Eli & Edythe L Broad Inst, Med Resequencing Project, Cambridge, MA 02142 USA

[48] MIT, Dept Biol, Cambridge, MA 02142 USA

[49] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA

[50] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

来源：

NATURE | 2008年 / 455卷 / 7216期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nature07385

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：

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

引用

页码：1061 / 1068

页数：8

共 51 条

[1] Cancer-specific mutations in PIK3CA are oncogenic in vivo [J].

Bader, AG ;

Kang, SY ;

Vogt, PK .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (05) :1475-1479

[2] Oncogenic PI3K deregulates transcription and translation [J].

Bader, AG ;

Kang, SY ;

Zhao, L ;

Vogt, PK .

NATURE REVIEWS CANCER, 2005, 5 (12) :921-929

[3] The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website [J].

Bamford, S ;

Dawson, E ;

Forbes, S ;

Clements, J ;

Pettett, R ;

Dogan, A ;

Flanagan, A ;

Teague, J ;

Futreal, PA ;

Stratton, MR ;

Wooster, R .

BRITISH JOURNAL OF CANCER, 2004, 91 (02) :355-358

[4] Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma [J].

Beroukhim, Rameen ;

Getz, Gad ;

Nghiemphu, Leia ;

Barretina, Jordi ;

Hsueh, Teli ;

Linhart, David ;

Vivanco, Igor ;

Lee, Jeffrey C. ;

Huang, Julie H. ;

Alexander, Sethu ;

Du, Jinyan ;

Kau, Tweeny ;

Thomas, Roman K. ;

Shah, Kinial ;

Soto, Horacio ;

Perner, Sven ;

Prensner, John ;

Debiasi, Ralph M. ;

Demichelis, Francesca ;

Hatton, Charlie ;

Rubin, Mark A. ;

Garraway, Levi A. ;

Nelson, Stan F. ;

Liau, Linda ;

Mischel, Paul S. ;

Cloughesy, Tim F. ;

Meyerson, Matthew ;

Golub, Todd A. ;

Lander, Eric S. ;

Mellinghoff, Ingo K. ;

Sellers, William R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (50) :20007-20012

[5] Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment [J].

Cahill, Daniel P. ;

Levine, Kymberly K. ;

Betensky, Rebecca A. ;

Codd, Patrick J. ;

Romany, Candice A. ;

Reavie, Linsey B. ;

Batchelor, Tracy T. ;

Futreal, P. Andrew ;

Stratton, Michael R. ;

Curry, William T. ;

Iafrate, A. John ;

Louis, David N. .

CLINICAL CANCER RESEARCH, 2007, 13 (07) :2038-2045

[6] Role of mismatch repair and MGMT in response to anticancer therapies [J].

Casorelli, Ida ;

Russo, Maria Teresa ;

Bignami, Margherita .

ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, 2008, 8 (04) :368-380

[7] Identification of noninvasive imaging surrogates for brain tumor gene-expression modules [J].

Diehn, Maximilian ;

Nardini, Christine ;

Wang, David S. ;

McGovern, Susan ;

Jayaraman, Mahesh ;

Liang, Yu ;

Alclape, Kenneth ;

Cha, Soonmee ;

Kuo, Michael D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (13) :5213-5218

[8] Alkylation damage in DNA and RNA -: repair mechanisms and medical significance [J].

Drablos, F ;

Feyzi, E ;

Aas, PA ;

Vaagbo, CB ;

Kavli, B ;

Bratlie, MS ;

Peña-Diaz, J ;

Otterlei, M ;

Slupphaug, G ;

Krokan, HE .

DNA REPAIR, 2004, 3 (11) :1389-1407

[9] AMPLIFIED AND REARRANGED EPIDERMAL GROWTH-FACTOR RECEPTOR GENES IN HUMAN GLIOBLASTOMAS REVEAL DELETIONS OF SEQUENCES ENCODING PORTIONS OF THE N-TERMINAL AND OR C-TERMINAL TAILS [J].

EKSTRAND, AJ ;

SUGAWA, N ;

JAMES, CD ;

COLLINS, VP .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (10) :4309-4313

[10] Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents [J].

Esteller, M ;

Garcia-Foncillas, J ;

Andion, E ;

Goodman, SN ;

Hidalgo, OF ;

Vanaclocha, V ;

Baylin, SB ;

Herman, JG .

NEW ENGLAND JOURNAL OF MEDICINE, 2000, 343 (19) :1350-1354

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