Intermediately Methylated Regions in Normal Cells Are Epimutation Hotspots in Cancer

DNA methylation is altered in all cancers, but the mechanisms responsible for these changes are not well understood. Using data from 100 primary samples, we show that regions with intermediate methylation in normal hematopoietic cells are hotspots for stable, clonal epimutations in acute myeloid leukemia. Analysis of hematopoietic stem cell clones demonstrated that intermediate methylation at epimutation hotspots reflects random allele-specific methylation and expression at the single cell level, representing a previously unrecognized form of somatically acquired imprinting. We identified somatically imprinted regions in other tissues and show they are epimutation hotspots in other cancer types. This demonstrates that random allele-specific methylation is both a general property of normal cells, and a vulnerability that renders them susceptible to cooperating events and clonal selection during cancer.