Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers

Abstract

Mutations in isocitrate dehydrogenases 1 and 2 (IDH^mut) are present in a variety of cancers, including glioma, acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma. These mutations promote hypermethylation, yet it is only a favorable prognostic marker in glioma, for reasons that are unclear. We hypothesized that the patterns of DNA methylation, and transcriptome profiles, would vary among IDH^mut cancers, especially gliomas. Using Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, we show that of 365,092 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDH^mut gliomas compared to wild-type (IDH^wt) gliomas, and only 3%, 2%, and 4% of CpG sites were hypermethylated in IDH^mut AML, melanoma, and cholangiocarcinoma, relative to each of their IDH^wt counterparts. Transcriptome differences showed pro-malignant genes that appear to be unique to IDH^mut gliomas. However, genes involved in differentiation and immune response were suppressed in all IDH^mut cancers. Additionally, IDH^mut caused a greater degree of hypermethylation in undifferentiated neural progenitor cells than in mature astrocytes. These data suggest that the extent and targets of IDH^mut-induced genomic hypermethylation vary greatly according to the cellular context and may help explain why IDH^mut is only a favorable prognostic marker in gliomas.