Cancer is both a genetic disease and an epigenetic diseases.Hallmarks of cancers include global DNA hypomethylation and local hypermethylation over promoters of tumor suppressor genes.Epigenetic therapies,including DNA methyltransferase inhibitors and HDAC inhibitors,have been thought to reactive tumor suppressor gene promoters to achieve efficacy.However,a comprehensive understanding of the impact of epimutations on cancer cells biology,both in the context of cancer cell abnormal DNA methylation and in the context of therapy induced DNA methylation changes,is still lacking.Using a comparative DNA methylomics approach,we profiled epimutations across multiple types of cancers as well as cancer cells under epigenetic therapy,and annotated these epimutations using the Human Reference Epigenome Maps produced by the Roadmap Epigenomics Consortium.Our results reveals that epimutations do not occur and cumulate randomely across cancer epigenome.Instead,they often occur in regulatory elements that normally specify cell fate,regardless of cell type from which the cancer is derived from,or unrelated cell type.Thus,the epimutation patterns of cancers suggest that cancer cells undergo identity crisis.This finding has potential implications in understanding the epigenetics impact on precision medicine,including how specific types of cancer cells metastasize,how they evade immune surveillance,and how therapies might take advance of the new identity cancer cells adopt to direct precision targeting.