Malignant astrocytomas: a system disease

JAMA A Network Model of a Cooperative Genetic Landscape in Brain Tumors Markus Bredel, MD, PhD; Denise M. Scholtens, PhD; Griffith R. Harsh, MD; Claudia Bredel, PhD; James P. Chandler, MD; Jaclyn J. Renfrow, MA; Ajay K. Yadav, PhD; Hannes Vogel, MD, PhD; Adrienne C. Scheck, PhD; Robert Tibshirani, PhD; Branimir I. Sikic, MD Context: Gliomas, particularly glioblastomas, are among the deadliest of human tumors. Gliomas emerge through the accumulation of recurrent chromosomal alterations, some of which target yet-to-be-discovered cancer genes. A persistent question concerns the biological basis for the coselection of these alterations during gliomagenesis. Objectives: To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance. Design, Setting, and Patients: Multidimensional genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA). Main Outcome Measures: Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival. Results: Gliomas select for a nonrandom genetic landscape—a consistent pattern of chromosomal alterations—that involves altered regions (“territories”) on chromosomes 1p, 7, 8q, 9p, 10, 12q, 13q, 19q, 20, and 22q (false-discovery rate-correctedP Conclusions: The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis. JAMA. 2009;302(3):261-275..