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.

Keywords: NGS; Soft tissue sarcoma; next generation sequencing; recurrence; targetable genetic alterations; undifferentiated pleomorphic sarcoma.

Figure 1. Landscape of genomic alterations in 16 patients with pre-recurrent UPS identified by targeted next-generation sequencing. Genomic alterations are annotated according to the color panel on the right of the image. Gene amplification (red), Substitution/Indel (green), Truncation (purple), Gene Homozygous Deletion (blue), Fusion/Rearrangement (orange). Alteration rates of genes are displayed on the left of the genomic alterations. Patient ID is shown on the bottom. A: Pre-recurrent UPS.

Figure 2. Landscape of genomic alterations in 16 patients with post-recurrent UPS identified by targeted next-generation sequencing. Genomic alterations are annotated according to the color panel on the right of the image. Gene amplification (red), Substitution/Indel (green), Truncation (purple), Gene Homozygous Deletion (blue), Fusion/Rearrangement (orange). Alteration rates of genes are displayed on the left of the genomic alterations. Patient ID is shown on the bottom. B: Post-recurrent UPS.

Figure 3. Landscape of genomic alterations in 16 paired pre-recurrent UPS and post-recurrent UPS identified by targeted next-generation sequencing. Gene alterations of 32 samples (16 paired) with no less than 2 in frequency were displayed. Genomic alterations were annotated according to the color panel on the right of the image: Gene amplification (red), Substitution/Indel (green), Truncation (purple), Gene Homozygous Deletion (blue), Fusion/Rearrangement (orange). Alteration rates of genes were displayed on the left of the genomic alterations. Patient ID is shown on the bottom. A: pre-recurrent UPS, B: post-recurrent UPS.

Figure 4. TMB is increased after tumor recurrence. (A) Comparison between the pre-recurrent UPS and post-recurrent UPS for TMB (mutations/MB). (B) Comparison of TMB between the pre-recurrent UPS and post-recurrent UPS according to patients who received treatment (chemotherapy and/or radiotherapy) or not in our hospital.