Ewing Sarcoma Tumors Characterized by Epigenetic Heterogeneity

A genomic analysis of Ewing sarcoma found substantial epigenetic heterogeneity both between tumors and within tumors, highlighting the need to consider non-genetic aspects in cancer biology and treatment.

Ewing sarcoma is defined and diagnosed based on the presence of the EWS-FLI1 fusion oncogene. “Despite this shared molecular basis, the clinical presentation and disease courses of patients with Ewing sarcoma vary,” wrote study authors led by Nathan C. Sheffield, PhD, of the University of Virginia in Charlottesville. “This heterogeneity is not reflected by the genetics of Ewing sarcoma, which is characterized by few somatic mutations and only three genes with recurrent genetic lesions (CDKN2A, STAG2, and TP53).”

The researchers hypothesized that the clinical heterogeneity may be due to epigenetic heterogeneity. They conducted DNA methylation sequencing in 140 Ewing sarcoma tumors, focusing on DNA methylation “as the classic epigenetic mark, which is intricately linked to cancer.” They examined epigenetic heterogeneity between cancers, between patients, and within individual tumors; the results were published online ahead of print in Nature Medicine.

They found that Ewing sarcoma tumors have a distinct DNA methylation signature, distinguished “with remarkable sensitivity and specificity” from various other cell types.

To compare to other cancer types, they calculated the coefficient of variation of DNA methylation levels. Ewing sarcoma fell into a medium-to-high range of this value, putting it on par with prostate cancer and chronic lymphocytic leukemia, both of which are genetically heterogeneous cancers of the elderly (as opposed to Ewing sarcoma, which has an average age of diagnosis of about 15 years). The tumors thus are characterized by a high degree of epigenetic heterogeneity, in sharp contrast with the malignancy’s genetic homogeneity.

They also used two different measures to assess intra-tumor variability. These both found high levels of heterogeneity, in similar ranges to other tumors with much more genetic heterogeneity than Ewing sarcoma. This was particularly true when patients had metastatic disease at the time of diagnosis.

“Our data thus support the conceptualization of Ewing sarcoma as an ‘enhancer disease,’ with widespread epigenomic reprogramming driven by EWS-FLI1,” the authors wrote. They also noted that this type of analysis should be useful for others studying the medical relevance of tumor heterogeneity, including the concept that “DNA methylation biomarkers can contribute to personalized cancer therapy.”