GENE-28. METHYLOMES AND TRANSCRIPTOMES VARY ACROSS IDH1 MUTANT CANCERS

Abstract

Since their discovery in gliomas, mutations in isocitrate dehydrogenases 1 and 2 (collectively referred to as “IDH1mut”) have been discovered in a variety of cancers, including acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma. While IDH1mut promotes genomic hypermethylation in all these cancers, glioma remains the only tumor in which IDH1mut is a consistently favorable prognostic marker, for reasons that are unclear. We therefore hypothesized that the pattern of DNA methylation, the resultant transcriptomic profiles, and specific genes suppressed, would all vary among IDH1mut cancers according to tissue of origin. We analyzed Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, including WHO grade II-IV gliomas (N=647; 427 IDH1mut, 220 IDH1wt), AML (N=194; 15 IDH1mut, 179 IDH1wt), melanoma (N=475; 23 IDH1mut, 452 IDH1wt), and cholangiocarcinoma (N=45; 7 IDH1mut, 38 IDH1wt). Using the tcgaWorkflow R package, we compared CpG methylation using Wilcoxon tests on beta values and transcriptomic read counts using negative binomial generalized log-linear models for IDH1mut versus IDH1wt tumors. A CpG site was considered hypermethylated if its mean beta value in IDH1mut cancer was >0.15 relative to the matching IDH1wt cancer. P-values were false discovery rate (FDR)-corrected. Of 264,735 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDH1mut gliomas compared to IDH1wt gliomas. In contrast, only 3%, 2%, and 4% of CpG sites were hypermethylated in IDH1mut AML, melanoma, and cholangiocarcinoma, relative to each of their IDH1wt counterparts. Methylation-associated transcriptome differences were also more pronounced in IDH1mut gliomas. Key promalignant genes that were uniquely hypermethylated and downregulated in IDH1mut gliomas, relative to other IDH1mut cancers, included ERBB2 (HER2), LGALS1 (galectin-1), and PDPN (podoplanin), among others. These data suggest that the extent and targets of IDH1mut-induced genomic hypermethylation vary greatly according to the cellular context, and may help explain why IDH1mut is only a favorable prognostic marker in gliomas.