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Non-invasive imaging can detect genetic mutations within a brain tumor

05/10/2012

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Researchers at Winship Cancer Institute have developed a technique for detecting an “oncometabolite”, a chemical produced by some brain tumors’ warped metabolism, via non-invasive imaging.

Their approach could allow doctors to know not only that a brain tumor is there, but also that it carries a particular genetic mutation. The researchers’ technique uses magnetic resonance spectroscopy (MRS) to measure a chemical, 2-hydroxyglutarate, which is scarce in normal tissues but produced by certain types of brain tumors carrying the mutations in an enzyme called isocitrate dehydrogenase (IDH) .

The results were published this week by the Journal of Molecular Medicine.

The research was a collaboration between the laboratories of Hui Mao, PhD, associate professor of radiology and imaging sciences and Emory University Center for Systems Imaging, and Erwin Van Meir, PhD, professor of neurosurgery and hematology and medical oncology. The first author of the paper is postdoctoral fellow Juliya Kalinina.  Emory undergraduate student, Anne Carroll, also contributed in this project.

"This is a significant advance, in that we can have a glimpse of genetic information into the human brain without actually having to do brain surgery,” Van Meir says.

 Emory team is one of several research groups independently obtained similar results recently.

http://www.ncbi.nlm.nih.gov/pubmed?term=idh1%20AND%20magnetic%20resonance%20spectroscopy

Mao: “This technique shows great potential for profiling a brain tumor based on its genetic and metabolic finger-prints and repeatedly and non-invasively monitoring tumor progression, helping physicians make decisions about chemotherapy and radiation, and possibly guiding treatment.”

 “The technique offers the possibility of following up the patient after surgery to see if the treatment is working, by monitoring the decline in levels of the oncometabolite,” Van Meir says.

Mutations in the genes IDH1 or IDH2 cause a distortion of cells’ metabolic cycles and the accumulation of 2-hydroxyglutarate. The presence of the mutations means patients generally survive longer, but they don’t respond as well to standard radiation and chemotherapy treatments.

Mutations in IDH1 or IDH2 (isocitrate dehydrogenase 1 or 2) are found in roughly 70 percent of low- and intermediate-grade gliomas, but usually not in primary forms of a more aggressive form of brain cancer, glioblastoma. Secondary glioblastomas that come from lower-grade gliomas do have the mutations. (Also found in AML)

To verify the test as a diagnostic tool, DNA from 65 glioma patients’ biopsy samples was analyzed; 39 had mutations in IDH. Magnetic resonance spectroscopic analysis of the samples could predict the presence of the mutation with 98 percent accuracy.

Recent research indicates that 2-hydroxyglutarate accumulation leads to the activation of genes that are usually shut off in healthy cells.  Several laboratories are looking for ways to reverse the metabolic changes in the IDH1/2-mutated cells as a form of targeted therapy.

The technique uses magnetic resonance imaging equipment that has already widely used in the hospitals for diagnostic imaging and radiological exams, but modifies the detection method in order to detect 2-hydroxyglutarate. No injections or special equipment would be needed for clinical use, Mao says.

“We wanted to establish the feasibility of detecting 2HG using FDA approved MRI scanners that are currently available in the clinic , over a time period that is tolerable to the patient – in about 20 or 30 minutes,” he says.

MRS has been used previously to monitor therapeutic progress for brain cancer patients. As a contrast to the 2-hydroxyglutarate technique, established methods measure the chemicals that are also presented in healthy tissues and cannot distinguish 2HG from the other chemicals in the brains.  

Funding from NCI, ACTSI, Georgia Cancer Coalition, Brain Tumor Funders Collaborative.

Reference:

J. Kalinina, A. Carroll, L. Wang, Q. Yu, D.E. Mancheno, S. Wu, F. Liu, J. Ahn, M. He, H. Mao and E.G. Van Meir. Detection of “oncometabolite” 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma. J. Mol. Med. (2012).