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

• DOI: 10.1073/pnas.0710052104
• Publication Date: 2007-12-07T01:44:47Z
• Authors: Rameen Beroukhim; Gad Getz; Leia Nghiemphu; Jordi Barretina; Teli Hsueh; David Linhart; Igor Vivanco; Jeffrey C. Lee; Julie H. Huang; Sethu Alexander; Jinyan Du; Tweeny Kau; Roman K. Thomas; Kinjal Shah; Horacio Soto; Sven Perner; John Prensner; Ralph M. Debiasi; Francesca Demichelis; Charlie Hatton; Mark A. Rubin; Levi A. Garraway; Stan F. Nelson; Linda Liau; Paul S. Mischel; Tim F. Cloughesy; Matthew Meyerson; Todd A. Golub; Eric S. Lander; Ingo K. Mellinghoff; William R. Sellers
• Keywords: Cell Line; Tumor, Chromosome Aberrations; statistics /&/ numerical data, Data Interpretation; Statistical, Glioma; genetics/pathology, Humans, Polymorphism; Single Nucleotide, Probability; Chromosome Aberrations; 0303 health sciences; 03 medical and health sciences; Cell Line, Tumor; Data Interpretation, Statistical; 610; Humans; Glioma; Polymorphism, Single Nucleotide; Probability; 3. Good health

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 ≈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 focalEGFRamplification: the broad events act in part through effects onMETand its ligandHGFand correlate with MET dependencein vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.