Mutational landscape of primary and recurrent Ewing sarcoma

Introduction: Ewing sarcoma (ES) is a highly aggressive malignancy of bone and soft tissues characterized by the presence of a genetic fusion involving the EWSR1 gene. More than one-third of patients develop distant metastases, which are associated with unfavorable prognosis. Knowledge about the disease's genetic landscape may help foster progress in using tar-geted therapies in the treatment of ES. Aim of the study: The objective is to assess the mutational landscape of ES in pretreatment samples, tumor sam -ples after neoadjuvant chemotherapy, and in metastatic/recurrent tumors in children and adults Material and methods: DNA from 39 for malin-fixed paraffin-embed-ded tumor samples of 22 patients (17 adults, 5 children) were analyzed by targeted next generation sequencing (NGS) using the Oncomine Compre-hensive Assay v3gene panel. Additional functional analyses were performed between patient subgroups. Results: All samples were character-ized by low tumor mutation burden (< 10 mut/Mb). The most commonly mutated genes were PIK3R1 (59%) and POLE (50%). The most widely detect-ed variants in biopsy samples were PIK3R1 T369I (50%), FGFR1 E159K, and TP53 at codon 72 (both in 27.3%). Ad-ditionally, the ATR, BRCA1, RAD50, ATM, CHEK1, and NBN genes showed a sig-nificantly higher number of mutations in ES. Mutations in PIK3R1 were signifi-cantly more frequent in adults, while mutations in the pathways responsible for cell cycle control, DNA repair, and transcriptional regulation were more frequent in children. Conclusions: Besides EWSR1 fusion, ES is characterized by numerous point mutations that are potential targets for precision medicine. There is high genomic heterogeneity that may ex-plain differences in outcomes between patient subgroups.