DNA mutations in tumors 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
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.
‘Ewing sarcoma showed unique characteristics that differ markedly from others cancers, and the DNA methylation patterns also varied between patients.’
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 Eleni Tomazou
from the St. Anna Children's Cancer Research Institute in Vienna
profiled many Ewing tumors. They found that the disease's clinical
diversity is reflected by widespread epigenetic heterogeneity.
Using novel bioinformatic methods developed by 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, 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", 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."