Science Times: Isocitrate Dehydrogenase Mutation Leads to Alteration in 3-Dimensional DNA Structure and Oncogene Activation in Gliomas

With approximately 18 000 diagnoses every year, gliomas represent the most common form of malignant brain tumors in adults. Despite the major investments and advances, overall outcomes in glioblastoma multiforme have not improved significantly. This stems in part from an inadequate understanding of the pathophysiology of gliomas. Molecular subgroups of gliomas have recently been identified that provide a better means of outcome prediction than classic histology. However, a major knowledge gap concerning why particular mutations form or drive further alterations in gene expression remains.

A better understanding of isocitrate dehydrogenase (IDH) provides a promising avenue because 80% of low- and moderate-grade gliomas demonstrate IDH mutations. Until recently, it was unclear why a mutation in a gene thought of as primarily a regulator of energy production and metabolism might hold such a key role. Mutant IDH proteins have a far-reaching effect by inhibiting the removal of DNA methylation, a critical step in the regulation of gene expression.1,2 Methyl groups can inhibit proteins from binding to DNA that may start or stop gene expression or lead to direct inactivation of tumor suppressor genes. This provides a plausible role for these alterations in IDH1 mutated tumors, but promoter hypermethylation has not necessarily been associated with changes in gene expression in these tumors.3,4 Additional regulation may come from the complex 3-dimensional structure of DNA that brings particular promoters, enhancers, and genes into close contact with each other. Contact domains, or these loops of chromatin, may allow distant regulators to come into close connection.5,6 CCCTC-binding factor (CTCF) creates insulation that separates these loops and has recently been shown to be methylation dependent.6,7

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