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Duke and Johns Hopkins universities make breakthrough discovery related to IDH gene mutation

and malignant glioma

DURHAM, N.C.—Scientists at Duke University Medical Center and Johns Hopkins University have discovered mutations in two genes—isocitrate dehydrogenase 1, gene 1 and 2 (IDH1 and IDH2)—that could be important therapeutic targets for the class of brain tumors known as malignant glioma, and perhaps other central nervous system cancers as well.

The research, published in the Feb. 19 issue of the New England Journal of Medicine, found IDH1 mutations in more than 70 percent of astrocytomas and olidgodendrogliomas, as well as in secondary glioblastoma multiforme (GBM). Those without the IDH1 mutation had similar mutations in the closely-related IDH2 gene, and these mutations decreased IDH enzymatic activity. As such, IDH mutations are likely important in initiating malignant gliomas.

Personalized medicine is one area this research may be a particular boon.

"IDH mutations appear to define a specific subtype of gliomas, so that we can plan specific treatment strategies to target this specific subtype of gliomas. Currently, for example, all glioblastoma patients are basically considered the same and are treated the same," notes Dr. Hai Yan, the study's lead author and an assistant professor in the Duke Department of Pathology. "What our studies have clearly demonstrated is that we need to start thinking about them differently. It is entirely possible, for example, that treatments that work for this specific subtype would not work for the rest of glioblastomas, or vice versa."

That very same insight could help vastly improve clinical trials for therapies aimed at glioma patients, Yan adds. Moreover, he notes, "we have now identified the very early genetic changes in the gliomas, which could serve as potential targets for drug discovery."

In addition, IDH can be used to distinguish primary GBMs, which do not arise from an existing tumor, from secondary GBMs, which arise from low-grade glioma tumors. The IDH1 mutation is missing in pilocytic astrocytomas, which means these particular brain tumors arise through a different mechanism, notes a Duke news release about the research findings.

Because the researchers found this genetic mutation in several different stages of glioma development, "the results suggested that the IDH mutations are the earliest genetic changes that start glioma progression," according to Dr. Darell Bigner, a co-author of the study and director of the Preston Robert Tisch Brain Tumor Center at Duke University.

Yet, patients with GBM or anaplastic astrocytoma who had the IDH mutations also were found to live longer than patients with those two cancers who lacked the mutations. So, malignant glioma appears to be two diseases, one that involves IDH mutations and one that doesn't, Yan says, noting, "As a cancer culprit gene, IDH mutations do contribute to cancer. Meanwhile, patients with the IDH mutation live longer with their cancer. The IDH mutation could serve as a biomarker that would help single out individuals who are likely to have better outcomes and receive different treatment.

"I can say this is potentially one of the most important discoveries in genetic studies on malignant gliomas, in the low-grade to high-grade forms of the tumor," Yan adds. "The results are so clear-cut. I have been doing intensive genetic studies in brain cancers for six years, and I have never seen gene mutations as striking as in this study." DDN



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