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Ewing Sarcomas Contain Spectrum of DNA Methylation Changes

NEW YORK (GenomeWeb) – An epigenetic analysis of Ewing sarcoma has found that while tumors of this cancer type share a certain DNA methylation signature, they also exhibit heterogeneity.

A team led by researchers at the CeMM Research Center for Molecular Medicine and St. Anna Children's Cancer Research Institute in Vienna examined DNA methylation within and between 140 Ewing sarcoma tumor samples. Ewing sarcoma, a bone cancer that affects children, is marked by an EWS-FLI1 fusion oncogene, but it otherwise has very few genetic changes that could account for differences in disease course.

As they reported in Nature Medicine this week, the researchers found that all Ewing sarcomas harbored a certain DNA methylation signature, but that they also fell along a continuum of DNA methylation differences. Epigenetic heterogeneity was particularly pronounced among patients with metastatic disease, the researchers noted.

"These new insights into the biology of Ewing sarcoma provide the basis for developing epigenetic biomarkers that can reliably predict disease course and therapy response," co-author Heinrich Kovar from St. Anna's said in a statement. "After two decades of stagnation in the therapy for patients with Ewing sarcoma, we expect new impulses for personalized therapy of this aggressive cancer."

Using reduced representation bisulfite sequencing (RRBS), Kovar and his colleagues generated DNA methylation maps for 140 Ewing sarcoma tumor samples. They compared these tumor profiles to a set of RRBS profiles from more than 50 cell types to uncover nearly 3,000 hypomethylated CpGs and 1,800 hypermethylated CpGs in Ewing sarcoma. These formed a DNA methylation signature that the tumors all shared and distinguished them from other cell types.

This signature included DNA hypomethylation surrounding the canonical EWS-FLI1 fusion oncogene, which previously has been linked to driving epigenetic reprogramming.

Despite the Ewing sarcoma tumor samples all sharing a DNA methylation signature, methylation patterns still varied between samples. Unexpectedly, the researchers said, these differences in DNA methylation didn't form disease subtype clusters. Instead, the team noted that the variations appeared to fall along a continuum of changes. This continuum appeared to be defined by two dimensions: one reflecting the extent to which the tumor epigenome has been reprogrammed and the other reflecting whether the tumor is more mesenchymal- or pluripotent stem cell-like.

This, the researchers said, supports the notion that Ewing sarcoma is an enhancer disease.

Ewing sarcoma tumor heterogeneity scores correlated with somatic mutations, tumor site, and metastatic status, the researchers further wrote. For instance, the 16 tumors in the sample with STAG2 mutations had lower tumor heterogeneity scores for EWS-FLI1-anti-correlated enhancers, placing these tumors toward the stem-like end of the spectrum. At the same time, higher intra-tumor heterogeneity scores were seen among tumors whose primary site was in the spine. In addition, intra-tumor heterogeneity scores were higher among patients whose disease was already metastatic at the time of diagnosis. This, the researchers added, supports the view that tumor heterogeneity is generally higher in more aggressive disease.

"Our findings in Ewing sarcoma also provide an interesting concept for other cancer with low genetic complexity," co-senior author Christoph Bock from CeMM added in a statement. "In the era of precision medicine, understanding the causes and consequences of tumor heterogeneity will be crucial to develop personalized therapies."