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Repurposing public sarcoma multi-omics for neoantigen discovery.

Panagiotis Mantas1, Karen A Krogfelt2

  • 1Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark. panman@dtu.dk.

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Summary

This study reanalyzes complex karyotype sarcomas (CKS) using advanced bioinformatics to identify potential immunotherapy targets. Even in "cold" tumors, patient-specific neoantigens can be found, offering new therapeutic avenues.

Keywords:
Complex karyotype sarcomasImmunogenomicsLegacy sequencingRNA-guided neoantigens

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Area of Science:

  • Cancer genomics
  • Immunotherapy biomarkers
  • Bioinformatics

Background:

  • Complex karyotype sarcomas (CKS) are immunologically "cold" due to structural instability, not high tumor mutational burden (TMB).
  • Public datasets offer potential for discovering immunotherapy biomarkers.
  • Whole-exome sequencing (WES) and RNA-sequencing are crucial for identifying neoantigens in CKS.

Purpose of the Study:

  • To overcome technical limitations in analyzing CKS patient data.
  • To identify and prioritize neoantigens for potential immunotherapy.
  • To uncover interpretable immunogenomic signals in complex karyotype sarcomas.

Main Methods:

  • Systematic immunogenomic reanalysis of a CKS patient cohort using a custom bioinformatics workflow.
  • Defining a quality-controlled "callable territory" and normalizing TMB metrics.
  • Integrating RNA-seq for expression filtering, variant transcription validation, and distinguishing amplification artifacts; applying a multi-modal epitope prediction pipeline.

Main Results:

  • Standard metrics often underestimated immunogenic potential in CKS.
  • Normalized TMB refined mutation burden estimates and improved low-coverage sample interpretation.
  • Transcriptomic data integration recovered actionable targets in "low-TMB" tumors, with fusion-derived peptides showing competitive binding affinities.

Conclusions:

  • Technically constrained multi-omic datasets can be re-analyzed to find therapeutic targets.
  • Patient-specific, expressed neoepitopes may exist in immunologically "cold" sarcomas.
  • Findings support looking beyond aggregate biomarkers to individual neoepitopes for sarcoma treatment.