Genomic co-genotype classification and clinical prognosis in Ewing sarcoma.

Abstract

e23532 Background: Ewing sarcoma is a highly aggressive round cell mesenchymal tumor that commonly occurs in children and young adults. It is molecularly characterized by chromosomal translocations, most commonly t (11;22), resulting in the abnormal EWSR1-FLI1 fusion. In addition to EWSR1-FLI1, patients may have other genomic variants that can be used for risk stratification. In the present study, we retrospectively investigated the association between co-variant genes and prognosis in patients with Ewing sarcoma. Methods: From 2019 to 2021, 10 patients with Ewing sarcoma were enrolled in the study, and their standard first-line treatment consisted of five-drug regimen chemotherapy including vincristine, doxorubicin (Adriamycin) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). We carried out whole-exome sequencing on collected tumor samples and matched leukocyte DNA from these patients. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. Results: In general, median progression-free survival (PFS) of the 10 confirmed Ewing sarcoma (with EWSR1-FLI1 fusion) patients was 10.5 months. We found that 60%, 30%, and 30% of patients had genetic variants (including mutation and copy number variation) in the three signaling pathways of cell cycle, WNT, and NOTCH, respectively. Their PFS was shorter than patients without these variants (log-rank test, p = 0.0345, 0.0053, and 0.0053, respectively). Median PFS was 7 vs 17 months in cell cycle pathway (the former with variants and the latter without variants), 5 vs 14 months in WNT pathway, and 5 vs 14 months in NOTCH pathway. However, there was no difference in PFS between patients with and without variants in other pathways (including TP53, RTK-RAS, MYC, DDR, PI3K) (log-rank test, p＞0.05). Conclusions: We found that the variants in cell cycle, WNT and NOTCH signaling pathway were associated with poor prognosis of Ewing sarcoma. This study provides important molecular markers for risk stratification in patients with Ewing sarcoma, which may provide insights into later clinical trials.