DNA damage in IDH-mutant gliomas: mechanisms and clinical implications

Purpose: Since the discovery of IDH mutations in glioma over a decade ago, significant progress has been made in determining how these mutations affect epigenetic, transcriptomic, and metabolic programs in brain tumor cells. In this article, we summarize current understanding of how IDH mutations influence DNA damage in glioma and discuss clinical implications of these findings. Methods: We performed a thorough review of peer-reviewed publications and provide an overview of key mechanisms by which IDH mutations impact response to DNA damage in gliomas, with an emphasis on clinical implications. Results: The effects of mutant IDH on DNA damage largely fall into four overarching categories: Gene Expression, Sensitivity to Alkylating Agents, Homologous Recombination, and Oxidative Stress. From a mechanistic standpoint, we discuss how mutant IDH and the oncometabolite (R)-2HG affect each of these categories of DNA damage. We also contextualize these mechanisms with respect to ongoing clinical trials. Studies are underway that incorporate current standard-of-care therapies, including radiation and alkylating agents, in addition to novel therapeutic agents that exert genotoxic stress specifically in IDH-mutant gliomas. Lastly, we discuss key unanswered questions and emerging data in this field that have important implications for our understanding of glioma biology and for the development of new brain tumor therapies. Conclusion: Mounting preclinical and clinical data suggest that IDH mutations alter DNA damage sensing and repair pathways through distinct mechanisms. Future studies are needed to deepen our understanding of these processes and provide additional mechanistic insights that can be leveraged for therapeutic benefit.