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

TLDR

Comprehensive knowledge of genomic alterations underlying cancer is critical for diagnostics, prognostics, and targeted therapeutics, yet systematic analysis is hampered by a lack of statistical frameworks to distinguish meaningful events from random background aberrations. The authors describe GISTIC, a systematic method for analyzing chromosomal aberrations in cancer. They applied GISTIC to 141 gliomas and compared the results with two prior studies. GISTIC identified about 35 concordant significant events (16–18 broad and 16–21 focal), half involving known cancer genes, and revealed distinct biological consequences such as broad chromosome‑7 amplification affecting MET/HGF signaling versus focal EGFR amplification, supporting systematic cancer genome characterization.

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 ≈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.