Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma

被引：816

作者：

Beroukhim, Rameen ^{[1
,2
,3
,4
,5
,6
,7
,8
,9
]}

Getz, Gad ^{[1
,2
]}

Nghiemphu, Leia ^{[10
,11
,12
,13
,14
]}

Barretina, Jordi ^{[1
,2
,3
,4
,5
]}

Hsueh, Teli ^{[10
,11
,12
,13
,14
]}

Linhart, David ^{[1
,2
,3
,4
,5
]}

Vivanco, Igor ^{[10
,11
,12
,13
,14
]}

Lee, Jeffrey C. ^{[1
,2
,3
,4
,5
]}

Huang, Julie H. ^{[10
,11
,12
,13
,14
]}

Alexander, Sethu ^{[1
,2
,3
,4
,5
]}

Du, Jinyan ^{[1
,2
,3
,4
,5
]}

Kau, Tweeny ^{[10
,11
,12
,13
,14
]}

Thomas, Roman K. ^{[1
,2
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,5
,15
,16
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,19
]}

Shah, Kinial ^{[1
,2
,3
,4
,5
]}

Soto, Horacio ^{[10
,11
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,14
]}

Perner, Sven ^{[6
,7
,20
]}

Prensner, John ^{[1
,2
,3
,4
,5
]}

Debiasi, Ralph M. ^{[1
,2
,3
,4
,5
]}

Demichelis, Francesca ^{[6
,7
]}

Hatton, Charlie ^{[1
,2
,3
,4
,5
]}

Rubin, Mark A. ^{[1
,2
,6
,7
,8
,9
]}

Garraway, Levi A. ^{[1
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,6
,7
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,9
]}

Nelson, Stan F. ^{[10
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]}

Liau, Linda ^{[10
,11
,12
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,14
]}

Mischel, Paul S. ^{[10
,11
,12
,13
,14
]}

Cloughesy, Tim F. ^{[10
,11
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,13
,14
]}

Meyerson, Matthew ^{[1
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,8
,9
]}

Golub, Todd A. ^{[1
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,8
,9
,21
,22
]}

Lander, Eric S. ^{[1
,2
,8
,9
,23
]}

Mellinghoff, Ingo K. ^{[24
,25
]}

Sellers, William R. ^{[1
,2
,3
,4
,5
,6
,7
,8
,9
,26
]}

机构：

[1] MIT, Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA

[2] Harvard Univ, Cambridge, MA 02142 USA

[3] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

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

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

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

[7] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

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

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

[10] Univ Calif Los Angeles, David Gaffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, David Gaffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[12] Univ Calif Los Angeles, David Gaffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA

[13] Univ Calif Los Angeles, David Gaffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[14] Univ Calif Los Angeles, David Gaffen Sch Med, Dept Neurosurg, Los Angeles, CA 90095 USA

[15] Univ Cologne, Max Planck Soc, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany

[16] Univ Cologne, Fac Med, D-50931 Cologne, Germany

[17] Univ Cologne, Max Planck Inst Neurol Res, D-50931 Cologne, Germany

[18] Univ Cologne, Dept Internal Med 1, D-50931 Cologne, Germany

[19] Univ Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany

[20] Univ Ulm, Dept Pathol, D-89070 Ulm, Germany

[21] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[22] Childrens Hosp, Dept Med, Boston, MA 02115 USA

[23] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[24] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA

[25] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[26] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 50期

关键词：

bioinformatics; comparative genomic hybridization; glioblastoma; copy-number alterations; single-nucleotide polymorphism arrays;

D O I：

10.1073/pnas.0710052104

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：

Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximate to 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focal EGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.

引用

页码：20007 / 20012

页数：6

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