Spectrum and Clinical Impact of Secondary Genetic Alterations in Translocation-Associated Sarcomas.

Abstract

Translocation-associated sarcomas (TASs) encompass a wide spectrum of pathologic entities and clinical behavior. Driven by the oncogenic fusion, TASs typically show a stable genome and a low tumor mutational burden (TMB), with infrequent secondary genetic alterations (SGAs). Although oncogenic/likely oncogenic SGAs have been associated with an aggressive clinical course in certain histotypes, a comprehensive comparative study of their clinical impact across TAS histotypes has not been performed to date. Herein, we investigate the genomic landscape of 632 TASs, spanning the most common histotypes: Ewing sarcoma (ES, n = 196), desmoplastic small round cell sarcoma (DSRCT, n = 115), solitary fibrous tumor (SFT, n = 87), synovial sarcoma (SS, n = 75), etc. All tumors were tested on a clinically validated, matched tumor-normal DNA-targeted next-generation sequencing panel, with confirmed gene fusion partners. Both gene-level and arm-level copy number alterations were assessed and correlated with survival. Overall, oncogenic SGAs were detected in 51% of patients, with the highest incidence in myxoid liposarcoma (MLS, 88%). Patients with oncogenic SGA had a higher TMB and were associated with distant metastasis and/or progression-free survival (PFS) in ES, SFT, SS, and MLS in the localized group. <i>TP53</i> mutations were the most common oncogenic SGAs across histotypes, with SFT and ES showing the highest rate (26% and 11%) and associated with worse PFS and disease-specific survival (<i>P</i> < .01). <i>TP53</i> mutations in ES (<i>P</i> < .01) and SFT (<i>P</i> = .045) and <i>TERT</i> promoter mutations in SFT (<i>P</i> < .001) and MLS (<i>P</i> = .049) correlated with metastasis in the localized group. Overall, oncogenic SGA correlated with a worse survival in certain TAS types.