Distinct metabolic hallmarks of WHO classified adult glioma subtypes

Abstract

Background Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy. Methods Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors - oligodendroglioma (n=31), astrocytoma (n=31) and glioblastoma (n=162) - were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation. Results Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue. Conclusion Key metabolic differences exist across adult glioma subtypes.

Does Blood-Brain Barrier Disruption Define the Glioma Extracellular Metabolome?

“…Lack of a metabolic signature of IDH-mutant gliomas beyond elevated 2-HG in our data could be due to a smaller cohort of patients lacking in low-grade astrocytomas. Indeed the clustering of grade 4 IDH-mutant astrocytomas with lower grade IDH-mutant gliomas in tissue metabolomic analyses was solely dependent on 2-HG 36 . Future studies will be needed to directly compare the extracellular versus tissue metabolome in paired patient samples.…”

“…S4B) . Recently published work from over 200 glioma tissues demonstrated significant metabolic heterogeneity in IDH-mutant gliomas and separation of IDH-mutant from IDH-WT tumors, albeit with fewer metabolites differentiating IDH-mutant grade 4 astrocytomas from GBMs 36 . Lack of a metabolic signature of IDH-mutant gliomas beyond elevated 2-HG in our data could be due to a smaller cohort of patients lacking in low-grade astrocytomas.…”

Cuproptosis key gene FDX1 is a prognostic biomarker and associated with immune infiltration in glioma

“…The results are consistent with previous. Meanwhile, we analyzed the expression of FDX1 protein in glioma cells by HPA (Human Protein Database) 8 . The results showed that FDX1 protein was expressed in the glioma cell line U251 cells, and was mainly expressed in the cytoplasm and cell membrane (Figure 2C).…”

“…Glioma is one of the most common central nervous system malignancies (1)(2)(3)(4)(5)(6). Evidence shows that high-grade glioma (HGG) has obvious aggressiveness and heterogeneity (7)(8)(9)(10)(11)(12)(13)(14). In 2022, the World Health Organization (WHO) updated the classification criteria of glioma according to the molecular characteristics of different gliomas, which will help patients obtain more accurate diagnoses and precise personalized treatment in clinical practice (1,2).…”

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

“…For example, after analyzing 224 different grades of glioma tissues, Bjorkblom et al found higher levels of glycine and 2-aminoadipic acid in IDH mutated higher-grade gliomas. In low-grade astrocytoma and oligodendroglioma, elevated N-acetyl aspartic acid was closely related to IDH mutations [ 103 ]. In the cerebrospinal fluid from patients with IDH mutated gliomas, alanine was usually decreased [ 104 ].…”