Ladies and gentlemen, dear colleagues, today I would like to share with you our study called IDH mutant gliomas differ in distribution of mitochondrial mutations. We have no disclosures. As you know, IDH mutations, which are the main driver events in astrocytomas and oligodendrogliomas, are associated with marked alterations in cellular metabolism. Here we hypothesized that these IDH-associated metabolic alterations would exert a purifying selection or an evolutionary advantage to certain mutations in the mitochondrial encoded genes, as these genes take part in energy metabolism of the cell. For this study, we used 59 adult epispheric diffused glioma samples. 29 of those tumors were IDH mutants, with the majority being lower-grade, and 30 were IDH wild-type tumors, with the majority being higher-grade tumors. Fresh frozen tumor samples and matched blood samples were subjected to DNA extraction and then to Illumina sequencing, and the sequences were analyzed using the Mitomap software. The mutation density for each mitochondrial gene was calculated and were compared for IDH mutant versus non-mutant tumors, wild-type tumors, and for lower-grade versus higher-grade tumors. When we looked at the mutation frequency, we found a total of 1531 variations at 469 unique positions. These were found in 59 different tumors. As is the case in most other cancers, we used the most common mutations in the D-loop region and the cytochrome b region. No other recurrent mutations, except for common polymorphisms, were encountered. When we compared the mutations that we found in mitochondrial genomes between IDH mutant and IDH wild-type tumors, we came across 7 mutations that were significantly more common in IDH mutant gliomas. Two of those were in the D-loop region and were previously shown in cancer. The other ones are unique mutations that were not previously shown in the literature. When we compared IDH mutant versus IDH wild-type tumors for mutational density in different mitochondrial genes, we came across significant differences in three mitochondrial genes, the ATP6, TR, and the ND6 genes, and the regulatory D-loop 1 region. The mutational density was slightly but significantly higher in IDH wild-type. When we compared low-grade tumors, this means WHO grade 2 tumors, versus high-grade tumors, this means WHO grade 3 or 4 tumors, we saw significant differences in mutation density in three mitochondrial genes, including TQ, again in the ATP6 gene, and again in the TR genes. There was no significant difference in the mutation density between low-grade and high-grade tumors. Studies on gliomas so far showed no canonical glioma-associated mutations in the mitochondrial genome. Our study also supported this notion. We also came across a significantly but slightly higher mutational frequency at the D-loop regulatory region in IDH wild-type gliomas. This was not unexpected, because this is the most commonly mutated region in all cancers, and it's also the most variable region of the mitochondrial genome. We also came across another alteration, the mitochondrial ATP6 gene mutations. The ATP6 gene mutation density was significantly higher, both in the IDH wild-type and also in higher-grade gliomas. This is a part of the mitochondrial ATP synthase complex, and the cause or the consequence is currently unknown, but is of significance for a future study. Finally, we wish to conclude that mutational densities in several mitochondrial-encoded genes differ between IDH mutant and IDH wild-type tumors, as well as tumors of lower-grade and higher-grade.

IDH mutant gliomas

mitochondrial mutations

cellular metabolism

glioma samples

mutation density