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Does Longitudinal Targeted Panel Sequencing Provide Clinically Relevant Information in Translocation-Associated

Mohamed A Yakoub1, Carla Saoud1, Damon R Reed2

  • 1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

JCO Precision Oncology
|April 23, 2026
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Summary

Sequential DNA sequencing in translocation-associated sarcomas (TAS) revealed acquired mutations, particularly TP53 alterations, after treatment. However, the clinical utility of repeated next-generation sequencing (NGS) in TAS remains unclear.

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Area of Science:

  • Oncology
  • Genetics
  • Molecular Pathology

Background:

  • Translocation-associated sarcomas (TAS) are diverse cancers defined by gene fusions and low tumor mutational burden (TMB).
  • RNA sequencing identifies gene fusions, while targeted DNA next-generation sequencing (NGS) detects actionable alterations and resistance mechanisms.

Purpose of the Study:

  • To investigate sequential targeted DNA sequencing in a large cohort of 108 TAS patients across six subtypes.
  • To identify acquired genetic alterations and their potential clinical relevance in TAS.

Main Methods:

  • Utilized sequential targeted DNA sequencing (Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets) in 108 TAS patients.
  • Analyzed longitudinal sequencing data to track genetic changes over time, often after systemic treatment and disease progression.

Main Results:

  • 53% of cases acquired new alterations, with 27% being oncogenic. TP53 alterations were the most common acquired mutations (10%), typically found in later assays.
  • Sequential NGS showed significantly higher mean mutation count, TMB, and fraction of genome altered compared to baseline.
  • While some alterations were actionable in other cancers, none were directly relevant for TAS treatment based on OncoKB levels 1-2.

Conclusions:

  • The study identified acquired genetic alterations in TAS, including TP53 mutations, after treatment.
  • Sequential NGS revealed increased genomic instability over time in TAS.
  • The clinical benefit and role of repeated NGS testing in managing TAS remain undetermined.