The epigenomics of sarcoma Nacev, Benjamin A.; Jones, Kevin B.; Intlekofer, Andrew M.; Yu, Jamie; Allis, C. David; Tap, William D.; Ladanyi, Marc; Nielsen, Torsten
Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity, and fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodeling, and modulation of the three-dimensional chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumor types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone posttranslational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodeling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumors ranging from chondroblastoma and giant cell tumor of bone to chondrosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma: all aggressive diseases which present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.
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