The DNA methylation landscape of five pediatric-tumor types

Abstract

Fewer DNA mutations have been identified in pediatric tumors than in adult tumors, suggesting that alternative tumorigenic mechanisms, including aberrant DNA methylation, may play a prominent role. In one epigenetic process of regulating gene expression, methyl groups are attached at the 5-carbon of the cytosine ring, leading to 5-methylcytosine (5mC). In somatic cells, 5mC occurs mostly in CpG islands, which are often within promoter regions. In Wilms tumors and acute myeloid leukemias, increased levels of epigenetic silencing have been associated with worse patient outcomes. However, to date, researchers have studied methylation primarily in adult tumors and for specific genes—but not on a pan-pediatric cancer scale. We addressed these gaps first by aggregating methylation data from 309 noncancerous samples, establishing baseline expectations for each probe and gene. Even though these samples represent diverse, noncancerous tissue types and population ancestral groups, methylation levels were consistent for most genes. Second, we compared tumor methylation levels against the baseline values for 489 pediatric tumors representing five cancer types: Wilms tumors, clear cell sarcomas of the kidney, rhabdoid tumors, neuroblastomas, and osteosarcomas. Tumor hypomethylation was more common than hypermethylation, and as many as 41.7% of genes were hypomethylated in a given tumor, compared to a maximum of 34.2% for hypermethylated genes. However, in known oncogenes, hypermethylation was more than twice as common as in other genes. We identified 139 probes (31 genes) that were differentially methylated between at least one tumor type and baseline levels, and 32 genes that were differentially methylated across the pediatric tumor types. We evaluated whether genomic events and aberrant methylation were mutually exclusive but did not find evidence of this phenomenon.