Mitochondrial Epigenetic Processes and Transfers in Chondrosarcoma Cancers with Mutant IDH2

Chondrosarcomas (CS), the most common form of bone cancer, can be extremely aggressive with high mortality rates. Therapeutic options for CS have not advanced in the last few decades, where resistance to chemo- and radiation therapy remains high, with surgery being the treatment regimen of choice for primary tumors. If tumors recur an estimated one third of patients will not survive due to metastatic spread. CS harbor mutations in either the isocitrate-dehydrogenase 1 (IDH1) gene or the IDH2 gene. While both mutants convert alpha-ketoglutarate (aKG) normally produced by chondrocytes, to D-2-hydroxyglutarate (D2HG), a potent oncometabolite, conversion by mutant IDH1 occurs in the cytosol whereas conversion by mutant IDH2 occurs in the mitochondria. D2HG is known to have a notable role in the carcinogenic processes of cells by inducing DNA and RNA methylation along with increases in genetic plasticity. We hypothesize that in IDH2 mutant cells, mitochondrial DNA (mtDNA) and RNA (mtRNA) are uniquely exposed to the oncometabolite D2HG, resulting in epigenetic changes to these nucleic acids, aberrant gene expression, and mitochondrial metabolism, all significantly associated with and ‘setting the stage’ for cancer progression/metastasis. Of further concern in CS expressing mutant IDH2 is the transfer of mitochondria, containing D2HG and D2HG-induced modifications, between cancerous and normal cells. The interplay between mtDNA and nuclear DNA (nDNA) becomes especially important in that nDNA methylation in a recipient cell may significantly alter gene expression, influencing cell physiology. These transfers, recently reported to have a critical role in disease progression and resistance, denote the importance of mitochondrial movement between cells via interconnecting nanotubes and vesicles in a cancer cells’ biology. This research is innovative in that the specific aims are to identify mitochondrial epigenetic carcinogenic processes occurring in IDH2 mutant CS cells, in comparison to both IDH1 mutant CS cells and their wild-type counterparts, which will serve as a biomarker and/or therapeutic target. The relative levels of mtDNA and mtRNA methylation, and mitochondrial gene expression profiles and metabolism will be determined, along with overall changes in nDNA histone modifications in IDH wild-type cells following transfection of mitochondria derived from IDH2 mutant cells. IDH2 gene mutations are early events in CS cancers, and it is crucial that these events are identified and understood prior to the onset of outcomes detrimental to the patient. Remarkably, because genetic mutations of IDH2 also occur in glioblastoma, the results from this proposal may significantly be applicable to other sarcomas.