|Title||Abstract 4431: Tandem profiling of 5-methyl and 5-hydroxymethylcytosine in glioblastoma identifies tumor-specific distribution of 5-hydroxymethylcytosine and associations with patient survival|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Johnson, KC, E Houseman, A, King, JE, Fadul, CE, Christensen, BC|
|Pagination||4431 - 4431|
Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. Genome-wide assessment of epigenetic alterations to cytosines in glioblastoma has largely been limited to 5-methylcytosine (5mC). 5-hydroxymethylcytosine (5hmC) is an additional cytosine modification that is deregulated in cancer, though the extent and context of these alterations at single cytosine resolution remain unclear. Through parallel processing of DNA with bisulfite and oxidative bisulfite treatments on Illumina 450K arrays we resolved both 5mC and 5hmC in 30 glioblastomas. We developed and applied a novel technique for estimating 5mC, 5hmC, and unmethylated proportions from array data to glioblastoma tissues and compare with normal brain tissue. Genomic distribution of 5hmC was associated with features of transcription despite the glioblastoma genome being relatively depleted of 5hmC. When integrating 5mC and 5hmC data using a Gaussian finite mixture model approach, we observed significant associations between 5hmC levels and gene-sets involved in immune and RNA regulatory processes while high 5mC classes were associated with receptor-mediated processes and cancer gene-sets. Significant differences in patient survival were observed among classes of 5hmC obtained from a recursively partitioned mixture model. Gene expression across epigenetic enzymes including methyltransferases and TETs was also investigated for relation with patterns and levels of 5hmC and 5mC. Analyses of elevated 5hmC with alternative splicing events that may promote disease progression are underway. Together, our results provide a genome-wide map of 5hmC in glioblastoma, indicate that transcription patterns as well as disrupted processes are associated with 5hmC patterns, and highlight the potential clinical prognostic utility of 5hmC in cancer.
|Short Title||Cancer Res|