EndocrinologyStudy Examines Mechanism For Gene Alterations In Brain Tumors
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-uniformly fatal brain tumors-often have both monosomy (absence of 1 chromosome) 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 [when a diploid cell (a cell having two sets of chromosomes) only has a single functional copy of a gene that does not produce enough of a gene product (typically a protein) to permit the cell to function normally, leading to an abnormal or diseased state] 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."
JAMA 2009;302[3]:276-289.
Journal of the American Medical Association