UC Irvine

Ewing Sarcoma (ES) is an aggressive, mesenchymal malignancy associated with a poor prognosis in the recurrent or metastatic setting with an estimated overall survival (OS) of <30% at 5 years. ES is characterized by a balanced, reciprocal chromosomal translocation involving the EWSR1 RNA-binding protein and ETS transcription factor gene (EWS-FLI being the most common). Interestingly, murine ES models have failed to produce tumors phenotypically representative of ES. Genomic alterations (GA) in ES are infrequent and may work synergistically with EWS-ETS translocations to promote oncogenesis. Aberrations in fibroblast growth factor receptor (FGFR4), a receptor tyrosine kinase (RTK) have been shown to contribute to carcinogenesis. Mouse embryonic fibroblasts (MEFs) derived from knock-in strain of homologous Fgfr4G385R mice display a transformed phenotype with enhanced TGF-induced mammary carcinogenesis. The association between the FGFRG388R SNV in high-grade soft tissue sarcomas has previously been demonstrated conferring a statistically significant association with poorer OS. How the FGFR4G388R SNV specifically relates to ES has not previously been delineated. To further define the genomic landscape and corresponding pathway alterations in ES, comprehensive genomic profiling (CGP) was performed on the tumors of 189 ES patients. The FGFR4G388R SNV was identified in a significant proportion of the evaluable cases (n = 97, 51%). In line with previous analyses, TP53 (n = 36, 19%), CDK2NA/B (n = 33, 17%), and STAG2 (n = 22, 11.6%) represented the most frequent alterations in our cohort. Co-occurrence of CDK2NA and STAG2 alterations was observed (n = 5, 3%). Notably, we identified a higher proportion of TP53 mutations than previously observed. The most frequent pathway alterations affected MAPK (n = 89, 24% of pathological samples), HRR (n = 75, 25%), Notch1 (n = 69, 23%), Histone/Chromatin remodeling (n = 57, 24%), and PI3K (n = 64, 20%). These findings help to further elucidate the genomic landscape of ES with a novel investigation of the FGFR4G388R SNV revealing frequent aberration.