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

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2007
Journal
Proc Natl Acad Sci U S A
Volume
104
Issue
50
Pages
20007-12
Date Published
2007 Dec 11
ISSN
1091-6490
URL
DOI
10.1073/pnas.0710052104
PubMed ID
18077431
PubMed Central ID
PMC2148413
Links
Grant list
K08 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