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 much 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 profiled many Ewing tumors. They found that the disease's clinical diversity is reflected by widespread epigenetic heterogeneity.
Using novel bioinformatic methods, 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.
"Our findings in Ewing sarcoma also provide an interesting concept for other cancer with low genetic complexity", Principal Investigator, 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."