Tumor cells may multiply quickly or slowly, and sow metastasis and dodge the immune system more or less strenuously. All this variability may be ascribed to genetic heterogeneity—but not always. Some cancers have low genetic complexity. For example, childhood cancers tend to harbor less genetic complexity than the cancers that afflict the elderly. And yet childhood cancers, like other cancers, manifest in diverse ways.

To what may the heterogeneity of childhood cancers be ascribed, if not genetic diversity? Epigenetic diversity, suggests a team of scientists based at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

The CeMM-led team recently completed a study of Ewing sarcoma, an aggressive bone cancer in children and adolescents. A single genetic defect—the EWS-ETS fusion—is present in all tumors, initiating cancer development and defining Ewing sarcoma as a disease. But the tumors carry very few DNA mutations that could explain the observed differences in the disease course of Ewing sarcoma patients.

After profiling many Ewing tumors, the scientists found that the disease's clinical diversity is reflected by widespread epigenetic heterogeneity. The scientists presented their results January 30 in the journal Nature Medicine, in an article entitled “DNA Methylation Heterogeneity Defines a Disease Spectrum in Ewing Sarcoma.”

The article described how the scientists performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels—between cancers, between tumors, and within tumors.

“We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma,” the authors of the Nature Medicine article wrote. “DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures.”

The scientists established that there is substantial epigenetic heterogeneity within Ewing sarcoma tumors, particularly in patients with metastatic disease. Moreover, the researchers found that Ewing sarcoma tumors appear to retain part of the characteristic DNA methylation patterns of their cell of origin.

The scientists suggest that the diverse clinical courses observed among Ewing sarcoma patients may be explained epigenetically: As DNA methylation influences gene activity, the combination of Ewing sarcoma specific and cell-of-origin specific patterns can lead to different outcomes. The epigenetic diversity also appears to correlate with the tumors' aggressiveness and metastatic state.

Regarding the future of Ewing sarcoma treatment, study co-director Heinrich Kovar, scientific director of St. Anna Children's Cancer Research Institute, optimistically stated: “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. After two decades of stagnation in the therapy for patients with Ewing sarcoma, we expect new impulses for personalized therapy of this aggressive cancer.”

“Our findings in Ewing sarcoma also provide an interesting concept for other cancer with low genetic complexity,” added Christoph Bock, principal investigator at CeMM and a co-director and corresponding author of the current study. “In the era of precision medicine, understanding the causes and consequences of tumor heterogeneity will be crucial to develop personalized therapies. Only with precise knowledge of the molecular mechanisms underlying each tumor can we hope to treat in a targeted way and with far fewer side effects.”








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