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New Gene Discoveries Hint at Therapies for Glioblastoma

For release: Tuesday, March 3, 2009

Scientists have long known that cancer results from an accumulation of genetic damage.  But despite decades of research, the list of known cancer related genes is surprisingly short.  

Equipped with powerful new technology, scientists recently began casting a wide net for genes involved in brain cancer.  In a study published in Science*, a team based at Johns Hopkins University in Baltimore found dozens of genes associated with an aggressive form of brain cancer called glioblastoma multiforme (GBM).

"This study is a goldmine for potential new therapies," says Gregory Riggins, M.D., Ph.D., a co-author of the study and a professor of neurosurgery and oncology at Johns Hopkins.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Cancer Institute (NCI).

GBM is the most frequent and deadly cancer affecting the brain.  With standard therapy, including surgery and chemotherapy, only about half of patients live more than 15 months beyond diagnosis.

Dr. Riggins and his colleagues acquired DNA from the tumors of 22 GBM patients, and scanned nearly the entire set of human genes for mutations (misspellings within the DNA code) and for copy number variations or CNVs (duplications or deletions of an entire gene).  They scanned a smaller set of genes from an additional 83 GBM samples.  They found that 42 genes harbored mutations or CNVs that were significantly associated with GBM.

Many of these genes were known offenders with roles in cellular growth, division, and DNA repair, all of which are pathways one would expect to go awry in a cell that is proliferating unchecked.  Somewhat unexpected was the finding that single tumors tended to have multiple gene defects affecting all three pathways.  The Cancer Genome Atlas (TCGA), a project sponsored by NCI and the National Human Genome Research Institute (NHGRI), found similar results, as reported in Nature.**

Those findings are helping reshape ideas about treatments for GBM.  Ongoing clinical studies have focused on single drug therapies aimed at single pathways, but researchers may need to start testing drug cocktails meant to target several different pathways at once, Dr. Riggins says. 

The Hopkins team also found some genes whose connection to GBM was previously unknown, which "gives us hope that there are some causes of GBM that we've been missing," Dr. Riggins says.  For instance, they discovered a link between GBM and genes involved in functions that are considered unique to the brain, such as electrical and chemical signaling by neurons.

Dr. Riggins says some of the newly discovered genes could also serve as markers and more precise therapeutic targets for unique subtypes of GBM.  For instance, the Hopkins team found that mutations in a gene called IDH1 might help distinguish primary and secondary GBM.  Primary GBM is detected as advanced cancer, while secondary GBM is detected as lower-grade cancer that progresses to advanced cancer.  Secondary GBM also tends to occur in younger patients.

"People in the field have believed for some time that secondary GBM is different from primary GBM at the molecular level; and we believe this gene helps explain the difference," says Dr. Riggins.

The IDH1 gene encodes a protein that helps relieve oxidative stress; it has not been previously associated with GBM.  The researchers found that 12 percent of the GBM samples they analyzed had mutations in IDH1, and that all of them affected an identical site within the IDH1 protein.  The mutations occurred predominantly in young patients with secondary GBM, affecting about 50 percent of patients under age 35 and 5 of 6 patients with secondary GBM, compared to 7 of 99 patients with primary GBM.

-By Daniel Stimson, Ph.D.

*Parsons et al.  "An Integrated Genomic Analysis of Human Glioblastoma Multiforme."  Science, September 26, 2008, Vol. 321, pp. 1807-1812.

**The Cancer Genome Atlas Network.  "Comprehensive Genomic Characterization Defines Human Glioblastoma Genes and Core Pathways."  Nature, October 23, 2008, Vol. 455, pp. 1061-1068.

Last Modified March 3, 2009