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Prospective Clinical Genomic Profiling of Ewing Sarcoma: ERF and FGFR1 Mutations as Recurrent Secondary Alterations
Koichi Ogura1,2, Arielle Elkrief1,2, Anita S Bowman1
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
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.
Insights
Genetic alterations in ERF and FGFR1 were identified as secondary drivers in Ewing sarcoma (ES). ERF loss promotes aggressive tumor biology by competing with EWSR1-FLI1, suggesting new therapeutic targets for ES.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Ewing sarcoma (ES) is a primitive sarcoma primarily driven by EWSR1-ETS fusions.
- Understanding cooperating secondary genetic alterations is crucial for defining ES pathobiology and treatment strategies.
Purpose of the Study:
- To define the landscape of cooperating secondary genetic alterations in a cohort of 113 patients with ES.
- To investigate the functional significance of ERF alterations in ES.
Main Methods:
- Clinical genomic profiling using a large-panel next-generation sequencing assay.
- Generation and analysis of ES cell lines with altered ERF expression (overexpression and knockdown).
- In vitro assays for cell viability, clonogenic growth, motility, transcriptomic, and epigenetic analyses, with in vivo xenograft validation.
Main Results:
- Recurrent secondary alterations in ERF (7%) and FGFR1 (2.7%) were identified as novel subsets in ES.
- ERF loss promoted cellular proliferation and clonogenic growth, associated with aggressive tumor biology pathways.
- Epigenetic studies revealed ERF competes with EWSR1-FLI1 at ETS-binding sites.
Conclusions:
- The study identifies ERF and FGFR1 as key secondary alterations in ES.
- Findings provide new insights into ES pathobiology and suggest novel therapeutic strategies targeting ERF in a subset of patients.
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