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Epigenetic Variation Defines a Disease Spectrum in Ewing Sarcoma

Tumors of the elderly, such as breast cancer and colon cancer, accumulate thousands of DNA mutations. These genetic defects contribute to cancer-specific properties including uncontrolled growth, invasion in neighboring tissues, and evasion from the immune system. Similar properties are also found in childhood cancers, although those tumors carry many fewer genetic defects, making it difficult to explain their clinical heterogeneity. This is particularly true for 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. Tackling this question, a team of scientists from Austria, France, Germany, and Spain led by Dr. Eleni Tomazou from the St. Anna Children's Cancer Research Institute in Vienna, Austria profiled many Ewing tumors. They found that the disease's clinical diversity is reflected by widespread epigenetic heterogeneity. Using novel bioinformatic methods developed by Dr. Nathan Sheffield at CeMM, the team studied the tumors' DNA methylation patterns - one of the most important facets of the human epigenome. Ewing sarcoma showed unique characteristics that differ markedly from others cancers, and the DNA methylation patterns also varied between patients. Moreover, the researchers found that Ewing sarcoma tumors appear to retain part of the characteristic DNA methylation patterns of their cell-of-origin. Thus, 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, Dr. 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,” Dr. Christoph Bock, Principal Investigator at CeMM, adds. "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, we can hope to treat in a targeted way and with far fewer side effects."

The new work was published online on January 30, 2017 in Naure Medicine. The article is titled “DNA Methylation Heterogeneity Defines a Disease Spectrum in Ewing Sarcoma.”

Dr. Kovar is a molecular biologist and the Scientific Director of St. Anna Children's Cancer Research Institute. He has been studying the molecular basis of bone cancer in children and adolescents for many years.

Dr. Tomazou is a senior Postdoc at the Lab of Heinrich Kovar at the St. Anna Children's Cancer Research Institute. She established epigenetic research at St. Anna and recently received an FWF Elise Richter grant for career development of female scientists in Austria.

Dr. Bock is a genome researcher and Principal Investigator at CeMM. His research focuses on the role of epigenetics in the development of disease. He also leads the joint Biomedical Sequencing Facility of CeMM and the Medical University Vienna.

The St. Anna Children's Cancer Research Institute (CCRI) (http://science.ccri.at) advances diagnostic, prognostic, and treatment strategies for children and adolescents suffering from cancer by supporting basic, translational, and clinical research into the specific features of different pediatric cancers, with the aim to make the most innovative treatment options available to young patients.

IMAGE

This image is an artistic rendering of a methylated DNA molecule. (Credit: Christoph Bock/CeMM).

[Press release] [Nature Medicine abstract]