Abstract
Ewing sarcoma is epigenetically heterogeneous despite the lack of genomic heterogeneity.
Major finding: Ewing sarcoma is epigenetically heterogeneous despite the lack of genomic heterogeneity.
Concept: DNA methylation occurs on a spectrum between mesenchymal and pluripotent stem cell signatures.
Impact: DNA methylation can measure epigenetic heterogeneity and may potentially predict aggressive disease.
Ewing sarcoma is a pediatric bone cancer characterized by a chromosomal translocation that produces the EWS–FLI1 fusion oncogene. These clinically heterogeneous tumors harbor few somatic mutations (with recurrent genetic alterations occurring only in CDKN2A, STAG2, and TP53), suggesting that epigenetic heterogeneity may explain the clinical presentation. Sheffield and colleagues performed DNA methylation sequencing of 140 Ewing sarcoma tumors and 16 Ewing sarcoma cell lines to characterize the interindividual and intratumor epigenetic heterogeneity, and compared the DNA methylation profiles with published data from other tumor types to determine the intercancer epigenetic heterogeneity. Ewing sarcomas clustered separately from other cancers based on DNA methylation profiles, due to a characteristic Ewing sarcoma methylation signature that distinguishes them from other tumor types. Ewing sarcomas exhibited a high level of interindividual heterogeneity, which occurred on an epigenetic continuum instead of clustering into discrete Ewing sarcoma subtypes. The tumors fell on a continuous disease spectrum between mesenchymal and pluripotent stem cell-like methylation signatures, and between more and less “Ewing-like” signatures based on the strength of the EWS–FLI1 regulatory signature. Ewing sarcomas also displayed high and variable intratumor heterogeneity. Genetic alterations correlated with DNA methylation heterogeneity, with STAG2-mutant tumors on average displaying more stem-like methylation signatures. Further, primary tumors from patients who had metastatic disease at diagnosis exhibited higher intratumor heterogeneity. In addition to identifying a characteristic Ewing sarcoma DNA methylation signature, these findings indicate that, despite the scarcity of genetic mutations, Ewing sarcomas exhibit high intratumor and intertumor epigenetic heterogeneity that may be linked with metastatic disease.
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