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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. This is an important step in developing more effective diagnosis and treatment," Dr. Zhang said. The study involved sequencing the complete normal and cancer genomes of 112 EWS patients, including children, teenagers, and young adults. "The Institut Curie is a reference center in France for Ewing sarcoma. Twenty-two years ago, my team identified the EWSR1-FLI1 gene fusion, a pathognomonic marker and a key pathogenic event in this disease. Thanks to this French-U.S. collaboration, we now have a more complete picture of the different genetic abnormalities that can be associated with EWSR1- FLI1 and may hence contribute to its aggressiveness. Hopefully, this may lead to improved treatment strategies," Dr. Delattre said. ES is identified in approximately 250 children and adolescents annually in the U.S., making it the second most common pediatric bone tumor. With current therapies, 75 to 80 percent of patients whose disease has not spread will become long-term survivors. But the prognosis is bleak for other patients. Nearly all ES begins with a chromosomal rearrangement that fuses part of the EWSR1 gene with a segment of FLI1 or a related gene. The fusion leads to production of an abnormal protein, which disrupts regulation of genes involved in cell growth and survival. The current study focused on identifying the genetic changes that follow the chromosomal rearrangement and help drive tumor formation. "Identifying these changes using whole genome sequencing and understanding how they alter survival can be critical to developing more effective treatments," said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at the Washington University School of Medicine in St. Louis. Whole-genome sequencing revealed that, unlike adult cancers, ES is characterized by relatively few mutations. The most commonly altered gene identified in this study was STAG2, which was mutated in 17 percent of the 112 tumors sequenced. The tumor suppressor gene TP53 was mutated in 7 percent of the tumors. When researchers checked for the alterations in 299 French ES patients, they found that STAG2 and TP53 mutations often occurred together and were associated with poor outcomes. Patients whose tumors include both mutations were far less likely than patients with neither mutation to be alive five years after their cancer was discovered. Mutations in either STAG2 or TP53 alone were not associated with a significantly worse outcome. TP53 is the most frequently altered gene in human cancer. STAG2 mutations have been identified in a variety of cancers, including the brain tumor glioblastoma, the skin cancer melanoma, and bladder cancer. In this study, the mutations inactivated the STAG2 gene. The gene carries instructions for assembling the STAG2 protein, which is part of a protein complex that ensures chromosomes separate normally during cell division. St. Jude researchers recently identified a promising three-drug combination therapy for ES with both STAG2 and TP53 mutations. The treatment combines the chemotherapy drugs irinotecan and temozolomide, which are already used to treat ES, with investigational drugs called PARP (poly ADP ribose polymerase) inhibitors. ES disappeared and did not return in more than 70 percent of mice treated with this combination therapy. Clinical trials of the combination therapies for treatment of ES are expected to open later this year at St. Jude and Dana-Farber/Harvard Cancer Center in Boston. The trials will involve ES patients whose cancer remained following standard therapy or has returned. In the current study, researchers detailed other insights regarding the role of STAG2 mutations in ES. The findings included evidence that the mutation was associated with relapse in several patients. While STAG2 and TP53 mutations frequently occurred together in ES, researchers found that mutations in STAG2 and the CDKN2A gene were usually mutually exclusive. CDKN2A carries instructions for making proteins that regulate cell division. Mutations in CDKN2A have been reported in ES and other cancers, but this is the first study to recognize that CDKN2A and STAG2 mutations rarely occur together in ES. The finding provides important insight into the tumor's genetic profile, which will aid efforts to develop more effective therapies. This study's first authors are Drs. Franck Tirode and Didier Surdez, both of Institut Curie. The other authors, not already mentioned, are Drs. Xiaotu Ma, Armita Bahrami, Zhaojie Zhang, Michael Rusch, Erin Hedlund, Gang Wu, Xiang Chen, Pankaj Gupta, Bhavin Vadodaria, John Easton, Sheila Shurtleff and James Downing, all of St. Jude; Dr. Michael Dyer, Howard Hughes Medical Institute (HHMI) and St. Jude; Drs. Matthew Parker and Gordon Lemmon, both formerly of St. Jude; Drs. Marie Cecile Le Deley and Odile Oberlin, both of Gustave Roussy, Paris; Drs. Eve Lapouble, Sandrine Grossetete-Lalami, Stephanie Reynaud, Thomas Rio-Frio, Gaelle Pierron, Sakina Zaidi, Valerie Laurence and Jean Michon, all of Institute Curie; Drs. Marta Gut and Ivo Gut, both of Centro Nacional de Analisis Genomico, Barcelona; Drs. Li Ding, Elaine Mardis, and Richard K. Wilson, of Washington University, St. Louis; and Perrine Marec-Berard, University of Lyon, Lyon, France. A second article, entitled “The Genomic Landscape of Pediatric Ewing Sarcoma,” is available in full-text in the same issue of Cancer Discovery and the link to this second article is also provided below. The Time Magazine cover shows an image of James Ewing, who was the first to describe Ewing sarcoma in 1921. [Press release] [Cancer Discovery abstract] [Cancer Discovery article]