gms | German Medical Science

Objective: Given the important role of IDH1/2 mutants for the diagnosis of low-grade gliomas (LGG), higher grade secondary gliomas (IDH_mG) and primary glioblastoma (GBM), we wondered whether other mitochondrial dehydrogenases are also differentially expressed in these tumor entities and are potentially contributing to different malignancy.

Methods: Using data from the TCGA and the GTex project, we analyzed expression of the 7 E1 subunits of the four mitochondrial 2-Oxo-Dehydrogenase complexes (2-ODHCs) in subtypes of LGG (Astrocytoma (AS; n=98), Oligoastrocytoma (OA; n=76) and Oligodendroglioma (OD; n=116)). In addition, we performed RT-qPCR, analyzing mRNA expression of the E1 subunits using 12 patients’ derived LGG-AS (1x Grade I; 4x Grade II and 7x Grade III), 16 primary GBM and 2 IDH_mG cell cultures comparing expression by using Welsh’s t-test.

Results: In silico analysis of the E1 subunits revealed significant downregulation of OGDHL and significant upregulation of DHTKD1 and BCKDHA in all LGG and of BCKDHB in OD compared to normal brain tissue (n=207). With regard to overall survival the most noticeable correlations were observed in Kaplan-Meyer Blots of AS (OGDH: Log rank (LR)=0.0073; hazard ratio (HR)=2.7; DHTKD1: LR=0.02; HR=0.43; BCKDHA: LR=0.007; HR=0.37; BCKDHB: LR=0.0048; HR=2.9). In OA all LRs were higher than 0.05 and in OD three genes exhibited significant LRs (OGDHL: LR=0.024; HR=0.34; DHTKD1: LR=0.026; HR=0.37; BCKDHB: LR=0.04; HR=0.43). Analysing the expression of E1 subunits in cell cultures revealed a ~2-fold higher expression of DHTKD1 in LGG-AS (p<2x10^-4) and IDH_mG (not significant) compared to primary GBM and a higher expression of OGDH in LGG-AS (~4-fold; p<2x10^-7) and IDH_mG (~5-fold; p<3.5x10^-3) compared to primary GBM. In addition, BCKDHB was ~2-fold higher expressed in LGG-AS (p<10^-6) and IDH_mG (not significant) compared to GBM.

Conclusion: Aside from the well described IDH1/2 mutations other mitochondrial dehydrogenase complexes contribute to malignancy of gliomas in an as yet unknown way. As the expression of some components correlates with overall survival it seems to be a worthwhile goal to further explore their role in tumour metabolism. Given the complex structures of the 2-ODHCs and their interplay in mitochondrial metabolism, an in-depth study of their function in individual brain tumours in general and in LGG in particular may also contribute to the development of new strategies for stratified therapies.