Secondary genomic alterations in Ewing sarcoma.

Abstract

11024 Background: Ewing sarcoma (ES) is the second most common bone cancer in children and young adults. The prognosis of recurrent or metastatic ES is poor, with a 5-year overall survival <30%. ES is characterized by translocations involving ETS transcription factors ( EWS– FLI and EWS– ERG translocations are the most common). Secondary somatic alterations in ES are infrequently described. Aberrations in fibroblast growth factor receptor 4 ( FGFR4), a receptor tyrosine kinase protein that plays an important role in cellular processes,have been shown to contribute to carcinogenesis in different types of cancer.More recently, the FGFR4-Gly388Arg (G388R) single nucleotide polymorphism (SNP), with the substitution of arginine instead of glycine in the transmembrane domain of the receptor, is found to significantly increase the risk of breast and prostate cancer. Mouse embryonic fibroblasts derived from knock-in strain of homologous FGFR4-G388R mice display a transformed phenotype, and TGFα-induced mammary carcinogenesis in this strain is significantly enhanced. The association between FGFR4 G338R SNP and ES has not been evaluated. We evaluated the frequency of FGFR4 G338R and whether comprehensive genomic profiling (CGP) might uncover additional, potentially targetable, genomic alterations (GA) in ES. Methods: Tissue from 253 patients with ES was assayed by hybrid-capture based CGP (FoundationOne Heme, next generation sequencing (NGS), analysis which includes both DNA sequencing of 406 genes and RNA sequencing of 265 genes), performed in the course of clinical care to evaluate GAs, including base substitutions, indels, amplifications, copy number alterations and gene fusions/rearrangements. Tumor mutational burden (TMB) was calculated from a minimum of 1.4 Mb sequenced DNA and reported as mutations/Mb. Microsatellite instability (MSI) status was determined by a novel algorithm analyzing 114 specific loci. Results: CGP identified several GAs in ES: TP53 (n= 50, 20%), MLL3 (n=15, 6%), MSH3 (n=14, 5%), ARID1A (n=11, 4%) and FGFR4 (n=3, 1%). FGFR4 G338R SNP was found in almost half of the patients (n=123, 49%). Conclusions: Secondary GAs in TP53, MLL3, MSH3, ARID1A and FGFR4 were found in more than one third of patients with ES (n=93, 37%). FGFR4 G388R SNP was detected in nearly half of patients, and may represent an alternative method of sarcomagenesis. Overall, the frequency of these GAs is significantly greater than previously reported. These GAs may inform the potential for targeted therapies.