Pathogenic and Targetable Genetic Alterations in Resected Recurrent Undifferentiated Pleomorphic Sarcomas Identified by Targeted Next-generation Sequencing

Abstract

Background/Aim: Undifferentiated pleomorphic sarcomas (UPSs) are difficult to treat, with a high recurrence rate. However, the genetic and molecular characterization of recurrent UPS has not been identified. Patients and Methods: In this study, we investigated the pathogenic and targetable genetic alterations in 16 paired locally pre-recurrent and post-recurrent UPS cases by targeted next-generation sequencing (466 genes). Results: Sequence variations were most frequently found in TP53 (66%), ATRX (34%), and RB1 (28%). In addition, for the first time, recurrent IL7R gene amplification (19%) and KMT2C gene mutation (16%) were detected in UPS. Interestingly, genetic alterations varied with tumor relapse. Importantly, targetable driver variants were found in recurrent UPS. Mutated genes were correlated with the cell cycle, PI3K/mTOR and RAS/MAPK signaling pathways. TMB was also found to be increased after tumor recurrence (4.6 vs. 7.5 mutations/MB, p=0.0343). Conclusion: Routine use of targeted next-generation sequencing for recurrent UPS can facilitate timely therapeutic decision-making.