Sarcoma Epigenomics: Chromatin Pathway Alterations as Diagnostic and Therapeutic Targets
This review details how epigenetic dysregulation including DNA methylation changes, histone mutations, and chromatin remodelling complex fusions drives tumorigenesis across multiple sarcoma subtypes. For pathology and molecular laboratories, epigenetic markers are becoming essential diagnostic tools: INI1/SMARCB1 loss defines epithelioid sarcoma, SS18-SSX fusions characterise synovial sarcoma, and H3K27 trimethylation loss identifies malignant peripheral nerve sheath tumours. These molecular features are both diagnostically required and increasingly predictive of response to emerging epigenetic therapies.
The original study
The epigenomics of sarcoma.
- Authors
- Nacev BA, Jones KB, Intlekofer AM, Yu JSE, Allis CD, Tap WD, et al.
- Journal
- Nature reviews. Cancer
- Type
- Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
- PMID
- 32782366
Original abstract
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 remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour 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 post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that 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.