Tumor cellular material may multiply quickly or slowly, and sow metastasis and dodge the immune system more or less strenuously. All this variability might be ascribed to genetic heterogeneity— but not always. Some malignancies have low genetic complexity. For example , childhood cancers often harbor less genetic complexity than the cancers that affect the elderly. And yet childhood cancers, like other cancers, express in diverse ways.
To what may the particular heterogeneity of childhood cancers be ascribed, if not hereditary diversity? Epigenetic diversity, suggests a team of researchers based at the CeMM Research Center for Molecular Medication of the Austrian Academy of Sciences.
The particular CeMM-led team recently completed a study of Ewing sarcoma, an aggressive bone cancer in children and children. A single genetic defect— the EWS-ETS fusion— is present in most tumors, initiating cancer development and defining Ewing sarcoma as a disease. But the tumors carry very few DNA variations 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 variety is reflected by widespread epigenetic heterogeneity. The researchers presented their results January 30 in the journal Character Medicine, in an article entitled “ DNA Methylation Heterogeneity Defines a Disease Spectrum in Ewing Sarcoma. ”
The article described how the scientists performed genome-scale GENETICS 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 in enhancers regulated by the disease-defining EWS-FLI1 fusion protein, hence establishing epigenomic enhancer reprogramming as an ubiquitous and feature of Ewing sarcoma, ” the authors from the Nature Medicine article wrote. “ DNA methylation variations between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory unique and a continuum between mesenchymal and stem cell signatures. ”
The scientists established that there is considerable epigenetic heterogeneity within Ewing sarcoma tumors, particularly within patients with metastatic disease. Moreover, the researchers discovered that Ewing sarcoma tumors appear to retain part of the feature DNA methylation patterns of their cell of origin.
The scientists suggest that the diverse clinical programs observed among Ewing sarcoma patients may be explained epigenetically: As DNA methylation influences gene activity, the mixture of Ewing sarcoma specific and cell-of-origin specific patterns can result in different outcomes. The epigenetic diversity also appears to assimialte with the tumors’ aggressiveness and metastatic state.
Regarding the future of Ewing sarcoma treatment, study co-director Heinrich Kovar, scientific director of St . Anna Kid’s Cancer Research Institute, optimistically stated: “These new information into the biology of Ewing sarcoma provide the basis designed for developing epigenetic biomarkers that can reliably predict disease training course and therapy response. After two decades of stagnation within the therapy for patients with Ewing sarcoma, we anticipate new impulses for personalized therapy of this aggressive malignancy. ”
“Our findings in Ewing sarcoma also provide an interesting concept for other cancer with reduced genetic complexity, ” added Christoph Bock, principal detective at CeMM and a co-director and corresponding author from the current study. “In the era of precision medication, understanding the causes and consequences of tumor heterogeneity is going to be crucial to develop personalized therapies. Only with precise understanding of the molecular mechanisms underlying each tumor can hopefully to treat in a targeted way and with far fewer negative effects. ”