Two Mutations Linked to Ewing Sarcoma Subtype with Poor Prognosis; New Combination Therapy May Be Effective

An international collaboration has identified frequent mutations in two genes that often occur together in Ewing sarcoma (ES) and that define a subtype of the cancer associated with reduced survival. The research, conducted by the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project and the Institut Curie-Inserm through the International Cancer Genome Consortium, appears in the November 2014 issue of Cancer Discovery. Mutations in the genes STAG2 and TP53 have previously been linked to ES. This is the first study, however, to show that patients whose tumors carry alterations in both genes are less likely to survive than are patients without the changes. The discovery stems from the most comprehensive analysis yet of the genetic makeup of ES, a cancer of the bone and soft tissue that primarily strikes children and adolescents. The findings come as St. Jude finalizes plans for clinical trials of an ES combination therapy. A recent St. Jude study showed that the combination therapy was effective in mice with ES that included both mutations. The agents work by damaging DNA or interfering with cellular repair mechanisms. "The current study used whole genome sequencing to define the most comprehensive landscape yet of the genetic alterations that contribute to the growth and recurrence of Ewing sarcoma," said Jinghui Zhang, Ph.D., a member of the St. Jude Department of Computational Biology. Dr. Zhang and Olivier Delattre, M.D., Ph.D., head of the genetic and biology of pediatric cancer group of Institut Curie, Paris, are the study's corresponding authors. "With the combined expertise of St. Jude and Institut Curie, we were able to identify a subtype with a dismal prognosis based on a tumor's genetic profile.
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