Gene Connections Key to Brain Tumor Growth
TUESDAY July 14, 2009 -- Researchers have identified a network of mutated genes and gene processes that, together, contribute to the development of glioblastomas, the deadliest type of brain tumor.
"There is not a single gene that accounts for the development of brain tumors," explained Dr. Markus Bredel, co-author of two related papers in the July 15 issue of the Journal of the American Medication Association. "It's the concert of those genes and the interaction of those genes that ultimately determine the progression of cancer."
Bredel, who is director of the Brain Tumor Institute Research Program at Northwestern University's Feinberg School of Medicine in Chicago, proposed that a combination of therapies targeting specific biological events might improve treatment outcomes for this type of cancer. Outcomes have remained stubbornly the same for about three decades.
"We hope that's the future of therapy -- that we can, over the long term, transfer this into a more chronic disease so patients could hopefully live 10 to 15 years," Bredel said. Development of a cure in that time frame is unlikely, he said.
People with glioblastomas now live an average of 12 to 14 months. U.S. Sen. Edward M. Kennedy (D-Mass.) was diagnosed in May 2008 with a malignant brain tumor.
"The authors have really made sense of these genetic changes and identified some of the pathways that seem to be crucial for glioblastoma development," said Dr. Boris Pasche, co-author of an accompanying editorial in the journal and associate director of the Comprehensive Cancer Center at the University of Alabama at Birmingham. "It's very exciting because it holds promise for identification of the Achilles' heel of this disease. If you can target several pathways that are implicated in a given disease, you can effectively change the course of the disease."
According to Bredel, up to 50 percent of the 30,000 to 40,000 genes in the human genome may be altered in glioblastoma.
The key is discovering which changes are actually important.
"Many of those changes will be just passengers or bystanders," Bredel said. "We tried to count up and prioritize the genes that are potentially the most important in glioblastoma disease and as a means to develop future therapy."
Starting with a genome-wide approach, using tissue from 501 people with this type of tumor, the researchers whittled their way down to 31 genes that appear to be the captains or godfathers of the complex genetic changes leading to glioblastoma.
These 31 genes were altered in up to 75 percent of glioblastomas, forming a landscape common to about three-quarters of all cases of glioblastoma, the study found.
And within those 31 genes, a subset of seven genes allowed the researchers to group the disease into low, intermediate and high risk in terms of outcome, a tool that may be useful for prognosis, they said.
Not only the genes were important, but the relationships between them were also critical, the researchers found.
In their second study, the researchers delved deeper into the mechanisms driving two of the 31 genes -- one so-called hub of genes and one gene that interacted with that hub, meaning those that have a high level of connectivity with the other genes.
The hub gene is the EGFR (epidermal growth factor receptor) oncogene on chromosome 7, according to the study. It is amplified in about 45 percent of glioblastoma cases, Bredel said. Oncogenes are genes that drive cancer growth.
The amplification seems to happen in parallel with a decrease in function in another gene, ANXA7, located on chromosome 10, the researchers reported. A decrease in the function of ANXA7 shoots the EGFR oncogene into overdrive, contributing to the development and progression of malicious glioblastomas, they found.
Pasche also said that the particular research approach used in the studies might push forward research into other cancers.
"My feeling is that this approach is novel and may indeed be successful in other tumor types that so far have been reluctant to give us their code," he said. "This is an appealing and promising approach to identify the language of tumors."
The U.S. National Cancer Institute has more on brain tumors.
Posted: July 2009
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