The interaction between a network of altered genes appears to play an important role in the development and progression of brain tumors, according to a study in the July 15 issue of JAMA.

Malignant gliomas are associated with disproportionately high illness and death and are among the most devastating of tumors. Particular genomic alterations are fundamental to both their formation and their malignant progression. "Chromosomal alterations presumably exert their tumor-promoting effect on glioma cells by modifying the expression or function of distinct genes, which map to those alterations, so as to deregulate growth factor signaling and survival pathways. For many chromosomal alterations, the biologically relevant target genes remain to be discovered," the authors write.

Oncogenic research on brain tumors has focused on the tumor-promoting or tumor-suppressive function of target genes within individual chromosomal alterations. However, these alterations do not exist in isolation, nor do single genes account for gliomagenesis. Rather, there may be mechanistic links to genes at other, coincident alterations, according to background information in the article.

Markus Bredel, M.D., Ph.D., of the Northwestern Brain Tumor Institute at Northwestern University Feinberg School of Medicine, Chicago, and colleagues examined the relationships of tumor-promoting genes in gliomas. The study included 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). The analysis included the identification of genes with coincident genetic alterations, correlated gene dosage (the copy number for a specific gene determined by certain analytic approaches) and gene expression, and multiple functional interactions; and the association between those genes and patient survival.

The researchers found: "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 [a consistent pattern of chromosomal alterations] during gliomagenesis, are associated with patient prognosis."

The authors add that the identification of such gene alterations in gliomas prompts evaluation of their potential as therapeutic targets. "The network context of a gene likely affects the efficacy of therapies that target its protein. The complexity of our landscape model helps explain the lack of therapeutic efficacy of strategies targeting single gene products."

A multigene risk-scoring model based on seven landscape genes was associated with the duration of overall survival in 189 glioblastoma patients from TCGA, an association that was confirmed in three additional malignant glioma patient populations.

"The current work provides a network model and biological rationale for the selection of a nonrandom genetic landscape in human gliomas," the authors write. "A multigene predictor model incorporating 7 landscape genes demonstrates how molecular insights emerging from our integrative multidimensional analysis could translate into relevant clinical end points affecting the future management of gliomas."

In a related article appearing in the July 15 issue of JAMA, researchers have identified the mechanism linked to the alteration of certain genes cited by Bredel et al in the previous study.

Glioblastomas often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7. This association suggests a fundamental biological role in glioblastoma pathogenesis, yet its molecular basis is poorly understood, according to background information in the article.

Markus Bredel, M.D., Ph.D., of the Northwestern Brain Tumor Institute at Northwestern University Feinberg School of Medicine, Chicago, and colleagues examined the mechanism of deregulation of the gene ANXA7 in glioblastomas and its association with patient outcome. The study included a multidimensional analysis of gene, coding sequence, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from U.S. medical centers and The Cancer Genome Atlas pilot project.

The authors write: "We propose that ANXA7 haploinsufficiency is a positive regulator of EGFR signaling and a driver for the conserved monosomy of chromosome 10 in glioblastomas. We provide evidence that ANXA7 loss of function facilitates unmitigated EGFR signaling, thereby contributing to an EGFR gain-of-function phenotype in high-grade gliomas, and that the complementary dysregulation of EGFR and ANXA7 synergistically promotes the tumorigenic potential of glioblastoma cells." The authors found that the status of the ANXA7 gene was immediately associated with the duration of survival of malignant gliomas in three patient populations.

"The dismal prognosis in glioblastoma outcome, even with the most advanced clinical care, addresses the need for the translation of new biological insights into clinical end points that can ultimately influence patient management. Identification of genes in which expression is altered or pathways in which activity is modified in tumors is important to understanding basic tumor biology, developing clinical-pathological correlations, and identifying points of therapeutic intervention. As we demonstrate here for ANXA7 and its link to EGFR signaling and dysregulation in glioblastomas, these require integration of genomic analysis, cancer genetics and biology, and clinical validation."

In an accompanying editorial, Boris Pasche, M.D., Ph.D., of the University of Alabama at Birmingham, and UAB Comprehensive Cancer Center, Birmingham, and Contributing Editor, JAMA, and Richard M. Myers, Ph.D., of the HudsonAlpha Institute for Biotechnology, Huntsville, Ala., comment on the findings of the studies in this week's JAMA on genetics and brain tumors.

"The potential clinical implications of these findings are significant. First, they highlight a pattern of codependent genetic interactions, which will need to be taken into account when designing novel therapeutic interventions in this otherwise therapy-refractory disease. Second, they provide a novel prognostic tool that may guide future therapeutic interventions."

"These 2 articles on glioblastoma multiforme are just the beginning, and many more reports on other cancers and other diseases are expected to be available in the near future; indeed, the amount of data and comprehensiveness of covering of the whole genome in such studies are expected to rapidly increase as the new DNA sequencing technologies improve even more. Once the new alphabet of these tumors is known, scientists will have the capability to decipher the language, which will usher in a new era in cancer research."