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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0710052104

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

Publication TypeJournal Article
Year of Publication2007
AuthorsBeroukhim, R, Getz, G, Nghiemphu, L, Barretina, J, Hsueh, T, Linhart, D, Vivanco, I, Lee, JC, Huang, JH, Alexander, S, Du, J, Kau, T, Thomas, RK, Shah, K, Soto, H, Perner, S, Prensner, J, Debiasi, RM, Demichelis, F, Hatton, C, Rubin, MA, Garraway, LA, Nelson, SF, Liau, L, Mischel, PS, Cloughesy, TF, Meyerson, M, Golub, TA, Lander, ES, Mellinghoff, IK, Sellers, WR
JournalProc Natl Acad Sci U S A
Volume104
Issue50
Pages20007-12
Date Published2007 Dec 11
ISSN1091-6490
KeywordsCell Line, Tumor, Chromosome Aberrations, Data Interpretation, Statistical, Glioma, Humans, Polymorphism, Single Nucleotide, Probability
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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=18077431
DOI10.1073/pnas.0710052104
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18077431?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18077431
PubMed Central IDPMC2148413
Grant ListK08 CA122833-01A1 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
K08 CA122833 / CA / NCI NIH HHS / United States
CA126546 / CA / NCI NIH HHS / United States
CA109038 / CA / NCI NIH HHS / United States
U24 CA126546 / CA / NCI NIH HHS / United States