Validation of In Vitro Trained Transcriptomic Radiosensitivity Signatures in Clinical Cohorts

John D O'Connor, Ian M Overton, Stephen J McMahon

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
13 Downloads (Pure)

Abstract

Transcriptomic personalisation of radiation therapy has gained considerable interest in recent years. However, independent model testing on in vitro data has shown poor performance. In this work, we assess the reproducibility in clinical applications of radiosensitivity signatures. Agreement between radiosensitivity predictions from published signatures using different microarray normalization methods was assessed. Control signatures developed from resampled in vitro data were benchmarked in clinical cohorts. Survival analysis was performed using each gene in the clinical transcriptomic data, and gene set enrichment analysis was used to determine pathways related to model performance in predicting survival and recurrence. The normalisation approach impacted calculated radiosensitivity index (RSI) values. Indeed, the limits of agreement exceeded 20% with different normalisation approaches. No published signature significantly improved on the resampled controls for prediction of clinical outcomes. Functional annotation of gene models suggested that many overlapping biological processes are associated with cancer outcomes in RT treated and non-RT treated patients, including proliferation and immune responses. In summary, different normalisation methods should not be used interchangeably. The utility of published signatures remains unclear given the large proportion of genes relating to cancer outcome. Biological processes influencing outcome overlapped for patients treated with or without radiation suggest that existing signatures may lack specificity.

Original languageEnglish
Article number3504
Pages (from-to)1-14
Number of pages14
JournalCancers
Volume15
Issue number13
DOIs
Publication statusPublished (in print/issue) - 5 Jul 2023

Bibliographical note

Funding Information:
UKRI Future Leaders Fellowship (MR/T021721/1; SMcM, IO).

Publisher Copyright:
© 2023 by the authors.

Keywords

  • gene signatures
  • radiosensitivity
  • transcriptomics

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