The Somatic Genomic Landscape of Glioblastoma

被引：4098

作者：

Brennan, Cameron W. ^{[1
,2
]}

Verhaak, Roel G. W. ^{[3
,12
]}

McKenna, Aaron ^{[4
]}

Campos, Benito ^{[5
,6
]}

Noushmehr, Houtan ^{[7
,8
]}

Salama, Sofie R. ^{[9
,10
]}

Zheng, Siyuan ^{[3
]}

Chakravarty, Debyani ^{[1
]}

Sanborn, J. Zachary ^{[9
,10
]}

Berman, Samuel H. ^{[1
]}

Beroukhim, Rameen ^{[4
,5
]}

Bernard, Brady ^{[11
]}

Wu, Chang-Jiun ^{[12
]}

Genovese, Giannicola ^{[12
]}

Shmulevich, Ilya ^{[11
]}

Barnholtz-Sloan, Jill ^{[13
]}

Zou, Lihua ^{[4
]}

Vegesna, Rahulsimham ^{[3
]}

Shukla, Sachet A. ^{[5
]}

Ciriello, Giovanni ^{[14
]}

Yung, W. K. ^{[15
]}

Zhang, Wei ^{[16
]}

Sougnez, Carrie ^{[4
]}

Mikkelsen, Tom ^{[17
,18
]}

Aldape, Kenneth ^{[16
]}

Bigner, Darell D. ^{[19
]}

Van Meir, Erwin G. ^{[20
,21
,22
]}

Prados, Michael ^{[23
]}

Sloan, Andrew ^{[24
]}

Black, Keith L. ^{[25
]}

Eschbacher, Jennifer ^{[26
]}

Finocchiaro, Gaetano ^{[27
]}

Friedman, William ^{[28
]}

Andrews, David W. ^{[29
]}

Guha, Abhijit ^{[30
]}

Iacocca, Mary ^{[31
]}

O'Neill, Brian P. ^{[32
,33
]}

Foltz, Greg ^{[34
]}

Myers, Jerome ^{[35
]}

Weisenberger, Daniel J. ^{[7
]}

Penny, Robert ^{[36
]}

Kucherlapati, Raju ^{[37
,38
]}

Perou, Charles M. ^{[39
]}

Hayes, D. Neil ^{[39
]}

Gibbs, Richard ^{[40
]}

Marra, Marco ^{[41
]}

Mills, Gordon B. ^{[42
]}

Lander, Eric ^{[4
]}

Spellman, Paul ^{[43
]}

Wilson, Richard ^{[44
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Weill Cornell Med Ctr, Dept Neurol Surg, Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[4] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA

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

[6] Univ Heidelberg Hosp, Dept Neurosurg, Div Expt Neurosurg, D-69120 Heidelberg, Germany

[7] Univ So Calif, Keck Sch Med, Univ Southern Calif Epigenome Ctr, Los Angeles, CA 90033 USA

[8] Univ Sao Paulo, Fac Med Ribeirao Preto, Ctr Integrat Syst Biol, Dept Genet, BR-14049900 Sao Paulo, Brazil

[9] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA

[10] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA

[11] Inst Syst Biol, Seattle, WA 98109 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[13] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA

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

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

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

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

[18] Henry Ford Hosp, Dept Neurosurg, Detroit, MI 48202 USA

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

[20] Emory Univ, Winship Canc Inst, Dept Neurosurg, Atlanta, GA 30322 USA

[21] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA

[22] Emory Univ, Sch Med, Atlanta, GA 30322 USA

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

[24] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Dept Neurosurg, Cleveland, OH 44106 USA

[25] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA

[26] St Josephs Hosp, Dept Pathol, Phoenix, AZ 85013 USA

[27] Ist Neurol Besta, Dept Neurooncol, I-20133 Milan, Italy

[28] Univ Florida, Dept Neurosurg, Gainesville, FL 32610 USA

[29] Thomas Jefferson Univ, Dept Neurol Surg, Philadelphia, PA 19107 USA

[30] Toronto Western Hosp, Dept Neurosurg, Toronto, ON M5T 2S8, Canada

[31] Helen F Graham Canc Ctr, Christiana Care, Dept Pathol, Newark, DE 19713 USA

[32] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA

[33] Mayo Clin, Ctr Canc, Rochester, MN 55905 USA

[34] Swedish Neurosci Inst, Ivy Brain Tumor Ctr, Seattle, WA 98122 USA

[35] Penrose St Francis Hlth Serv, Dept Pathol, Colorado Springs, CO 80907 USA

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

[37] Brigham & Womens Hosp, Boston, MA 02215 USA

[38] Harvard Univ, Sch Med, Boston, MA 02215 USA

[39] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[40] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

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

[42] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[43] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA

[44] Washington Univ, Genome Inst, St Louis, MO 63110 USA

[45] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA

来源：

CELL | 2013年 / 155卷 / 02期

基金：

美国国家卫生研究院;

关键词：

COPY-NUMBER ALTERATION; DRIVER MUTATIONS; EGFR; EXPRESSION; PATHWAYS; GLIOMAS; KINASE; PDGFRA; GENES; GRADE;

D O I：

10.1016/j.cell.2013.09.034

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

引用

页码：462 / 477

页数：16

共 50 条

[1]

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status [J].

Bady, Pierre ;

Sciuscio, Davide ;

Diserens, Annie-Claire ;

Bloch, Jocelyne ;

van den Bent, Martin J. ;

Marosi, Christine ;

Dietrich, Pierre-Yves ;

Weller, Michael ;

Mariani, Luigi ;

Heppner, Frank L. ;

Mcdonald, David R. ;

Lacombe, Denis ;

Stupp, Roger ;

Delorenzi, Mauro ;

Hegi, Monika E. .

ACTA NEUROPATHOLOGICA, 2012, 124 (04) :547-560

[2]

MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004) [J].

Bartel, David P. .

CELL, 2007, 131 (04) :11-29

[3]

Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[4]

Melanoma genome sequencing reveals frequent PREX2 mutations [J].

Berger, Michael F. ;

Hodis, Eran ;

Heffernan, Timothy P. ;

Deribe, Yonathan Lissanu ;

Lawrence, Michael S. ;

Protopopov, Alexei ;

Ivanova, Elena ;

Watson, Ian R. ;

Nickerson, Elizabeth ;

Ghosh, Papia ;

Zhang, Hailei ;

Zeid, Rhamy ;

Ren, Xiaojia ;

Cibulskis, Kristian ;

Sivachenko, Andrey Y. ;

Wagle, Nikhil ;

Sucker, Antje ;

Sougnez, Carrie ;

Onofrio, Robert ;

Ambrogio, Lauren ;

Auclair, Daniel ;

Fennell, Timothy ;

Carter, Scott L. ;

Drier, Yotam ;

Stojanov, Petar ;

Singer, Meredith A. ;

Voet, Douglas ;

Jing, Rui ;

Saksena, Gordon ;

Barretina, Jordi ;

Ramos, Alex H. ;

Pugh, Trevor J. ;

Stransky, Nicolas ;

Parkin, Melissa ;

Winckler, Wendy ;

Mahan, Scott ;

Ardlie, Kristin ;

Baldwin, Jennifer ;

Wargo, Jennifer ;

Schadendorf, Dirk ;

Meyerson, Matthew ;

Gabriel, Stacey B. ;

Golub, Todd R. ;

Wagner, Stephan N. ;

Lander, Eric S. ;

Getz, Gad ;

Chin, Lynda ;

Garraway, Levi A. .

NATURE, 2012, 485 (7399) :502-506

[5]

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

[6]

Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and Associated Genomic Alterations [J].

Brennan, Cameron ;

Momota, Hiroyuki ;

Hambardzumyan, Dolores ;

Ozawa, Tatsuya ;

Tandon, Adesh ;

Pedraza, Alicia ;

Holland, Eric .

PLOS ONE, 2009, 4 (11)

[7]

CALLAGHAN T, 1993, ONCOGENE, V8, P2939

[8]

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].

Chapman, Paul B. ;

Hauschild, Axel ;

Robert, Caroline ;

Haanen, John B. ;

Ascierto, Paolo ;

Larkin, James ;

Dummer, Reinhard ;

Garbe, Claus ;

Testori, Alessandro ;

Maio, Michele ;

Hogg, David ;

Lorigan, Paul ;

Lebbe, Celeste ;

Jouary, Thomas ;

Schadendorf, Dirk ;

Ribas, Antoni ;

O'Day, Steven J. ;

Sosman, Jeffrey A. ;

Kirkwood, John M. ;

Eggermont, Alexander M. M. ;

Dreno, Brigitte ;

Nolop, Keith ;

Li, Jiang ;

Nelson, Betty ;

Hou, Jeannie ;

Lee, Richard J. ;

Flaherty, Keith T. ;

McArthur, Grant A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516

[9]

STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA [J].

Chen, An-Jou ;

Paik, Ji-Hye ;

Zhang, Hailei ;

Shukla, Sachet A. ;

Mortensen, Richard ;

Hu, Jian ;

Ying, Haoqiang ;

Hu, Baoli ;

Hurt, Jessica ;

Farny, Natalie ;

Dong, Caroline ;

Xiao, Yonghong ;

Wang, Y. Alan ;

Silver, Pamela A. ;

Chin, Lynda ;

Vasudevan, Shobha ;

DePinho, Ronald A. .

GENES & DEVELOPMENT, 2012, 26 (13) :1459-1472

[10]

Glioblastoma-Derived Epidermal Growth Factor Receptor Carboxyl-Terminal Deletion Mutants Are Transforming and Are Sensitive to EGFR-Directed Therapies [J].

Cho, Jeonghee ;

Pastorino, Sandra ;

Zeng, Qing ;

Xu, Xiaoyin ;

Johnson, William ;

Vandenberg, Scott ;

Verhaak, Roel ;

Cherniack, Andrew D. ;

Watanabe, Hideo ;

Dutt, Amit ;

Kwon, Jihyun ;

Chao, Ying S. ;

Onofrio, Robert C. ;

Chiang, Derek ;

Yuza, Yuki ;

Kesari, Santosh ;

Meyerson, Matthew .

CANCER RESEARCH, 2011, 71 (24) :7587-7596

← 1 2 3 4 5 →