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Network of altered genes may play role in brain cancer development
Biological mechanism behind gene alteration identified.
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Findings from two studies recently published in the Journal of the American Medical Association have identified and validated altered gene networks that may play a key role in the development and progression of glioblastomas.
Identifying which genetic abnormalities act as contributors to disease development and progression remains a challenge in cancer research, according to Boris Pasche, MD, PhD, and Richard M. Myers, PhD. The studies may be a start to understanding tumor biology and ultimately identifying targets of therapeutic intervention.
“These two 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 the whole genome in such studies is expected to rapidly increase as the new DNA sequencing technologies improve even more,” Pasche and Myers said in an accompanying editorial.
Pasche is director of the division of hematology and oncology at the University of Alabama at Birmingham, and Myers is president and director at HudsonAlpha Institute for Biotechnology, in Huntsville, Ala.
Genetic landscape identified
In the first study, Markus Bredel, MD, PhD, of the Northwestern Brain Tumor Institute at Northwestern University Feinberg School of Medicine, and colleagues studied the genomic profiles of 501 patients with gliomas from multiple U.S. academic centers and from The Cancer Genome Atlas Pilot Project. Forty-five tumors were from an initial discovery set between 2001 and 2004, and 456 tumors were from validation sets between 2006 and 2008.
Researchers hypothesized that employing a systems biology approach to distinguish genetic changes would reveal a non-random genetic landscape, a consistent pattern of altered chromosomes, that facilitate gliomagenesis cooperatively. The primary outcome was the identification of genes with coincident alterations, correlated gene dosage and gene expression, and multiple functional interactions. Researchers examined the association between the identified genes and patients’ survival as well.
A multi-gene risk-scoring model based on seven landscape genes — POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7 and PDCD4 — was associated with duration of survival in 189 patients with glioblastoma. This association was confirmed in three other independent studies of patients with glioma.
“We show that a focused set of seven landscape genes associates with patient survival across several different study populations with discrimination similar to that of correlative multigene predictors,” the researchers wrote.
“These observations lay the foundation for future development of a mechanistically based molecular risk estimation model in glioblastomas and high-grade gliomas,” they added.
ANXA7, EGFR relationship examined
In a companion study, the researchers examined the relationship between two highly interactive genes — annexin A7 (ANXA7) and epidermal growth factor receptor (EGFR).
Glioblastomas typically have monosomy of chromosome 10 and gains of EGFR gene locus on chromosome 7; however, the mechanism behind this is poorly understood, according to researchers.
They conducted a multidimensional analysis of gene, coding sequence, messenger RNA transcript, protein data for ANXA7 and EGFR and clinical patient data profiles for 543 high-grade gliomas. Partial loss of ANXA7 was mimicked by inhibiting gene expression. Researchers analyzed the effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival and the effect of loss of ANXA7 and gain of EGFR on tumorigenesis.
The findings showed that glioblastoma multiforme cells with reduced ANXA7 expressed higher levels of EGFR and had increased tumorigenicity. Additionally, cells with decreased ANXA7 enhanced EGFR signaling.
In examining a possible cooperative effect between loss of ANXA7 and gain of EGFR, findings demonstrated a tumorigenic synergism between loss of ANXA7 and amplification of EGFR.
“The potential clinical implications of these findings are significant,” Pasche and Myers said. “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.” – by Christen Haigh
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