title: Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.
abstract: 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 approximately 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 focalEGFR 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.
authors: Broad Institute, Massachusetts Institute of Technology and Harvard University, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors: Rameen
authors: R
authors: Beroukhim
authors: Gad
authors: G
authors: Getz
authors: Leia
authors: L
authors: Nghiemphu
authors: Jordi
authors: J
authors: Barretina
authors: Teli
authors: T
authors: Hsueh
authors: David
authors: D
authors: Linhart
authors: Igor
authors: I
authors: Vivanco
authors: Jeffrey C
authors: JC
authors: Lee
authors: Julie H
authors: JH
authors: Huang
authors: Sethu
authors: S
authors: Alexander
authors: Jinyan
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authors: Du
authors: Tweeny
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authors: Kau
authors: Roman K
authors: RK
authors: Thomas
authors: Kinjal
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authors: Shah
authors: Horacio
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authors: Soto
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authors: Perner
authors: John
authors: J
authors: Prensner
authors: Ralph M
authors: RM
authors: Debiasi
authors: Francesca
authors: F
authors: Demichelis
authors: Charlie
authors: C
authors: Hatton
authors: Mark A
authors: MA
authors: Rubin
authors: Levi A
authors: LA
authors: Garraway
authors: Stan F
authors: SF
authors: Nelson
authors: Linda
authors: L
authors: Liau
authors: Paul S
authors: PS
authors: Mischel
authors: Tim F
authors: TF
authors: Cloughesy
authors: Matthew
authors: M
authors: Meyerson
authors: Todd A
authors: TA
authors: Golub
authors: Eric S
authors: ES
authors: Lander
authors: Ingo K
authors: IK
authors: Mellinghoff
authors: William R
authors: WR
authors: Sellers
mesh_terms: D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011336:Probability