Analysis of Cerebrospinal Fluid for D-2-Hydroxyglutarate May Detect Malignant Brain Tumors Nonsurgically
When a brain tumor is suspected, its presence is usually confirmed by anatomic imaging such as computed tomography (CT) or magnetic resonance imaging (MRI). But through imaging, not much about the tumor molecularly can be learned. Surgery and a biopsy are necessary to get a glimpse of the cancer cells themselves.
This may change with the prior discovery that some brain tumors have mutations that alter cancer cell metabolism, producing a distinctive chemical or “oncometabolite” (D-2-hydroxyglutarate) that can be seen via metabolic imaging noninvasively. The levels of this chemical are much lower in normal brain cells.
Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have shown that D-2-hydroxyglutarate can also be detected in cerebrospinal fluid (CSF). Scientists analyze the CSF using mass spectrometry, which is many times more sensitive than imaging techniques. Their findings were published by Kalinina et al in Clinical Cancer Research.
Study Findings
The authors describe their mass spectrometry-based approach as complementary to the detection of D-2-hydroxyglutarate by imaging. Although it is somewhat more invasive to draw CSF, it has advantages over imaging and could be used repeatedly to track the effectiveness of anticancer treatment.
“These findings further demonstrate the potential of CSF as a source for brain tumor biomarkers that could be useful for diagnosis, prognosis, and monitoring of treatment efficacy, thus providing a window on brain tumor biology without the need for repeated surgical tumor sampling,” said Dr. Van Meir, who is Professor of Neurosurgery and Hematology and Medical Oncology at Emory University School of Medicine, leader of the Cancer Cell Biology Program at Winship Cancer Institute, and founding Director of Emory's graduate program in cancer biology.
The mutations that cause the alterations in metabolism are in the genes for isocitrate dehydrogenase (IDH1 or IDH2) and are found in more than 75% of low- and intermediate-grade gliomas and 10% of glioblastomas. The D-2-hydroxyglutarate appears to warp how the cancer cell maintains genes as activated or repressed.
Patients with tumors bearing these mutations have improved overall survival compared with similar brain tumors without them, but they are less responsive to standard radiation and chemotherapy treatment. Development of drugs that target the mutated IDH1 and IDH2 enzymes is underway.
The mass spectrometry approach was validated by testing CSF samples from 3 cohorts of cancer patients (84 patients total), obtained from Penn State; the University of Massachusetts Medical School; the University of Mainz; the University of California, San Diego; and Utah's Huntsman Cancer Center. The average level of D-2-hydroxyglutarate in CSF was 17 times higher in patients with IDH mutations than in those without them.
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