Abstract
Mutations in isocitrate dehydrogenases 1 and 2 (IDHmut) 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 IDHmut 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 IDHmut gliomas compared to wild-type (IDHwt) gliomas, and only 3%, 2%, and 4% of CpG sites were hypermethylated in IDHmut AML, melanoma, and cholangiocarcinoma, relative to each of their IDHwt counterparts. Transcriptome differences showed pro-malignant genes that appear to be unique to IDHmut gliomas. However, genes involved in differentiation and immune response were suppressed in all IDHmut cancers. Additionally, IDHmut caused a greater degree of hypermethylation in undifferentiated neural progenitor cells than in mature astrocytes. These data suggest that the extent and targets of IDHmut-induced genomic hypermethylation vary greatly according to the cellular context and may help explain why IDHmut is only a favorable prognostic marker in gliomas.
Highlights
Epigenetic modifications control gene expression via mechanisms that are highly coordinated throughout the life of a cell
The glioma cohort included 647 patients that consisted of World Health Organization (WHO) grade II-IV gliomas (427 IDHmut and 220 IDHmut gliomas compared to wild-type (IDHwt))
The acute myeloid leukemia (AML) cohort included 194 patients (15 IDHmut and 179 IDHwt), The Cancer Genome Atlas (TCGA) had 45 cholangiocarcinomas (7 IDHmut and 38 IDHwt), and melanomas consisted of 475 cases (23 IDHmut and 452 IDHwt)
Summary
Epigenetic modifications control gene expression via mechanisms that are highly coordinated throughout the life of a cell. Methylation of a CpG site within or near a gene can change its expression, usually by suppressing it. If this happens to a tumor-suppressor gene, oncogenesis may occur[2]. The mechanisms by which aberrant methylation occurs, and its consequences in cancer, are becoming better understood One such mechanism involves point mutations in isocitrate dehydrogenases 1 and 2 (collectively “IDHmut”). Methylation and suppression of the gene encoding TF, F3, is far greater in IDHmut gliomas than in other IDHmut cancers[18,19]. This prompted a broader comparative analysis of the major IDHmut cancers in The Cancer Genome Atlas, demonstrating great diversity in DNA methylation patterns, resultant transcriptomic profiles, and specific genes and biological pathways altered by IDHmut depending on cellular context
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