Abstract
Patients with malignant gliomas have a poor prognosis with average survival of less than 1 year. Whereas in other tumor entities the characteristics of tumor metabolism are successfully used for therapeutic approaches, such developments are very rare in brain tumors, notably in gliomas. One metabolic feature characteristic of gliomas, in particular diffuse astrocytomas and oligodendroglial tumors, is the variable content of D-2-hydroxyglutarate (D2HG), a metabolite that was discovered first in this tumor entity. D2HG is generated in large amounts due to various “gain-of-function” mutations in the isocitrate dehydrogenases IDH1 and IDH2. Meanwhile, D2HG has been detected in several other tumor entities, including intrahepatic bile-duct cancer, chondrosarcoma, acute myeloid leukemia, and angioimmunoblastic T-cell lymphoma. D2HG is barely detectable in healthy tissue (<0.1 mM), but its concentration increases up to 35 mM in malignant tumor tissues. Consequently, the “oncometabolite” D2HG has gained increasing interest in the field of tumor metabolism. To facilitate its quantitative measurement without loss of spatial resolution at a microscopical level, we have developed a novel bioluminescence assay for determining D2HG in sections of snap-frozen tissue. The assay was verified independently by photometric tests and liquid chromatography/mass spectrometry. The novel technique allows the microscopically resolved determination of D2HG in a concentration range of 0–10 μmol/g tissue (wet weight). In combination with the already established bioluminescence imaging techniques for ATP, glucose, pyruvate, and lactate, the novel D2HG assay enables a comparative characterization of the metabolic profile of individual tumors in a further dimension.
Highlights
Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases (IDHs) 1 and 2 (IDH1 and IDH2) have been identified during exome-sequencing studies of glioblastoma tumors in 2008 [1]
Regardless of the overall frequency, the type of IDH mutations differs in the described tumor entities: in astrocytoma and oligodendroglioma, more than 90% of all IDH mutations are of the IDH1R132H type [3], whereas the second most frequent type is IDH1R132C
In angioimmunoblastic T-cell lymphoma, mutations are found most frequently in IDH2 [10]. 2-HG has been described initially in the context of hereditary 2-HG aciduria in 1980. 2-HG aciduria is caused by germline loss-of-function mutations in either D-2-hydroxyglutarate dehydrogenase (D2-Hydroxyglutarate dehydrogenase (HGDH)) or L-2-hydroxyglutarate dehydrogenase (L2-HGDH) [13,14,15,16,17]
Summary
Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases (IDHs) 1 and 2 (IDH1 and IDH2) have been identified during exome-sequencing studies of glioblastoma tumors in 2008 [1]. These mutations can be found in approximately 75% of diffuse astrocytoma and oligodendroglioma tumors [2,3,4]. In 20% of acute myeloid leukemia (AML) [5, 6], 50% of chondrosarcoma [7, 8], 20% of intrahepatic cholangiocarcinoma [9], and 20% of angioimmunoblastic T-cell lymphoma, IDH1 or IDH2 are mutated as well [10]. In angioimmunoblastic T-cell lymphoma, mutations are found most frequently in IDH2 [10]. 2-HG has been described initially in the context of hereditary 2-HG aciduria in 1980. 2-HG aciduria is caused by germline loss-of-function mutations in either D-2-hydroxyglutarate dehydrogenase (D2-HGDH) or L-2-hydroxyglutarate dehydrogenase (L2-HGDH) [13,14,15,16,17]
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