Gene Sequencing Projects Link Two Mutations to Ewing Sarcoma Subtype With Poor Prognosis


Key Points

  • The study found that the most common mutations in Ewing sarcoma, STAG2 and TP53, often occurred together and were associated with poor outcomes.
  • Mutations in either STAG2 or TP53 alone were not associated with a significantly worse outcome.
  • Mutations in STAG2 and CDKN2A were usually mutually exclusive.

An international collaboration has identified frequent mutations in two genes that often occur together in Ewing sarcoma 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, was reported by Crompton et al in Cancer Discovery.

“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, PhD, a member of the St. Jude Department of Computational Biology.

“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. Mutations in the genes STAG2 and TP53 have previously been linked to Ewing sarcoma, but this is the first study to show that patients whose tumors carry alterations in both genes are less likely to survive than are patients without the changes.

Study Details

The study involved sequencing the complete normal and cancer genomes of 112 Ewing sarcoma patients, including children, teenagers, and young adults, and 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 coauthor Richard K. Wilson, PhD, Director of The Genome Institute at Washington University School of Medicine in St. Louis.

Whole-genome sequencing revealed that unlike adult cancers, Ewing sarcoma is characterized by relatively few mutations. The most commonly altered gene identified in this study was STAG2, which was mutated in 17% of the 112 tumors sequenced. The tumor-suppressor gene TP53 was mutated in 7% of the tumors.

When researchers checked for the alterations in 299 French Ewing sarcoma 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 5 years after their cancer was discovered. Mutations in either STAG2 or TP53 alone were not associated with a significantly worse outcome.

Other findings regarding the role of STAG2 mutations in Ewing sarcoma included included evidence the mutation was associated with relapse in several patients.

While STAG2 and TP53 mutations frequently occurred together in Ewing sarcoma, researchers found that mutations in STAG2 and the tumor-suppressor gene CDKN2A were usually mutually exclusive.Mutations in CDKN2A have been reported in Ewing sarcoma and other cancers, but this is the first study to recognize that CDKN2A and STAG2 mutations rarely occur together in Ewing sarcoma. The finding provides important insight into the tumor’s genetic profile, which will aid efforts to develop more effective therapies.

Promising Combination Therapy

St. Jude researchers recently identified a promising three-drug combination therapy for Ewing sarcoma with STAG2 and TP53 mutations. The treatment combines the drugs irinotecan and temozolomide, which are already used to treat Ewing sarcoma, with investigational PARP inhibitors. Ewing sarcoma disappeared and did not return in more than 70% of mice treated with the combination therapy.

Clinical trials of the combination therapies for treatment of Ewing sarcoma are expected to open later this year at St. Jude and Dana-Farber/Harvard Cancer Center in Boston. The trials will involve Ewing sarcoma patients whose cancer remained following standard therapy or has returned.

Dr. Zhang and Olivier Delattre, MD, PhD, of Institut Curie, Paris, are the corresponding authors for the Cancer Discovery article.

In the United States, the research was supported in part by the Pediatric Cancer Genome Project, the National Cancer Institute, the National Institutes of Health, the Howard Hughes Medical Institute, and ALSAC. In Europe, the project was supported in part by the French National Cancer Institute, Inserm, the National Research Agency for Science Projects, the Canceropôle Île-de-France, the French League Against Cancer, European PROVABES, ASSET, EEC, and the Institute Curie-SIRIC.

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