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

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.