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Teams Explore Epigenetic Consequences of Mutating Cancer-Associated Enzyme

NEW YORK (GenomeWeb News) – A trio of new studies in Nature are highlighting the ties between genetic mutations and epigenetic alterations in cancer — particularly the genome-wide methylation and transcriptional changes associated with mutations to the IDH1, a gene coding for the metabolic enzyme isocitrate dehydrogenase.

In the first of these, researchers from Memorial Sloan-Kettering Cancer Center and the Weill Cornell College of Medicine compared methylation patterns in nerve cells with or without IDH1 mutations. They found that, over time, IDH1 mutations cause methylome remodeling, leading to the so-called CpG island methylator phenotype, or CIMP, seen in some forms of glioma.

"Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers," co-corresponding authors Ingo Mellinghoff and Timothy Chan and their colleagues wrote.

Alterations in IDH1 and another isocitrate dehydrogenase gene, IDH2, have been detected in sequencing studies of glioma, glioblastoma, acute myeloid leukemia, and other cancers, the team explained. And at least some tumor sub-groups appear to be characterized by both IDH1 mutation and glioma-CIMP — hypermethylation that is especially common at sites in the genome that are rich in cytosine and guanine residues.

The relationship between the IDH1 mutation, genome-wide methylation changes, and tumor formation are not entirely clear, though, fueling interest in mechanisms that may link the processes.

In an effort to understand the epigenetic consequences of IDH1 mutation, Mellinghoff, Chan, and colleagues used Illumina's Infinium HumanMethylation450 array to look at genome-wide methylation patterns in astrocyte cells with or without a glioma-associated substitution in IDH1.

The mutation they tested, at a site coding for arginine 132 in the IDH1 enzyme's active site, is by far the most common IDH1 mutation detected in glioma, authors noted.

In astrocytes that had been passaged as many as 50 times, researchers found distinct genome-wide methylation patterns depending on whether cells had wild type or mutant IDH1. In particular, they saw a jump in methylation at nearly 31,000 CpG sites in astrocytes containing the IDH1 mutation.

When they turned their attention to a set of low-grade glioma samples, researchers saw that almost all of the tumors with hypermethylation, G-CIMP related phenotypes, and G-CIMP transcriptional profiles also contained glitches in either IDH1 or IDH2.

A series of transcriptome, chromatin immunoprecipitation, and other experiments supported the team's notion that mutations in IDH1 cause methylation remodeling that eventually produce tumors with G-CIMP features.

Moreover, their results hint that these changes may reflect a decline in 5-hydroxymethylcytosine, a modification that usually helps keep DNA methylation in check. Indeed, they reported, astrocytes containing mutant IDH1 also had lower-than-usual levels of 5-hmC.

In an accompanying Nature study, meanwhile, some members of the same group took a closer look at how IDH1 or IDH2 mutations can impact histone methylation and demethylation-related processes in cells.

In particular, results of that study indicate that 2-hydroxyglutarate, a metabolic compound produced by mutated forms of the IDH1 and IDH2 enzymes, interferes with histone demethylation in a way that can hamper cellular differentiation in both tumor and non-transformed cells.

Finally, a Finnish, American, and Canadian group delved into some of the biochemical details of 2-hydroxyglutarate production by mutant IDH1 and IDH2 enzymes in a third Nature study. That work looked at the downstream effects of altering not only IDH enzymes, but also other metabolic enzymes implicated in cancer.

That team reported that that the form of 2-hydroxyglutarate produced by IDH1/2 mutants is capable of activating a cell proliferation-promoting pathway in astrocyte cells that hinges around EGLN hydroxylase enzymes.

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