Key result
Prospective clinical genomic profiling of 113 patients with Ewing sarcoma identified recurrent secondary alterations in ERF in 7% of patients and FGFR1 in 2.7% of patients.
Why the study?
To better define the landscape of cooperating secondary genetic alterations in Ewing sarcoma.
Observational (n=113)
No
Clinical genomic profiling of Ewing sarcoma identified recurrent ERF loss-of-function mutations and FGFR1 activating mutations, with ERF loss functionally driving increased tumorigenic properties.
Answers are grounded in this paper and cite their sources.
ERF and FGFR1 alterations may identify therapeutic subsets; leaves open clinical actionability pending prospective validation.
PURPOSE Ewing sarcoma (ES) is a primitive sarcoma defined by EWSR1-ETS fusions as the primary driver alteration. To better define the landscape of cooperating secondary genetic alterations in ES, we analyzed clinical genomic profiling data of 113 patients with ES, a cohort including more adult patients (> 18 years) and more patients with advanced stage at presentation than previous genomic cohorts. METHODS The data set consisted of patients with ES prospectively tested with the US Food and Drug Administration–cleared Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets large panel, hybrid capture-based next-generation sequencing assay. To assess the functional significance of ERF loss, we generated ES cell lines with increased expression of ERF and lines with knockdown of ERF. We assessed cell viability, clonogenic growth, and motility in these ES lines and performed transcriptomic and epigenetic analyses. Finally, we validated our findings in vivo using cell line xenografts. RESULTS Novel subsets were defined by recurrent secondary alterations in ERF, which encodes an ETS domain transcriptional repressor, in 7% of patients (five truncating mutations, one deep deletion, and two missense mutations) and in FGFR1 in another 2.7% (one amplification and two known activating mutations). ERF alterations were nonoverlapping with STAG2 alterations. In vitro, increased expression of ERF decreased tumor cell growth, colony formation, and motility in two ES cell lines, whereas ERF loss induced cellular proliferation and clonogenic growth. Transcriptomic analysis of cell lines with ERF loss revealed an increased expression of genes and pathways associated with aggressive tumor biology, and epigenetic, chromatin-based studies revealed that ERF competes with EWSR1-FLI1 at ETS-binding sites. CONCLUSION Our findings open avenues to new insights into ES pathobiology and to novel therapeutic approaches in a subset of patients with ES.
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Ogura et al. (2022) conducted an observational in Ewing Sarcoma (n=113). ERF and FGFR1 mutations vs. Wild-type tumors was evaluated on Frequency of ERF and FGFR1 mutations. Prospective clinical genomic profiling of 113 patients with Ewing sarcoma identified recurrent secondary alterations in ERF in 7% of patients and FGFR1 in 2.7% of patients.
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