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

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.