Genome-wide variation in cell-free DNA end motif entropy predicts immunotherapy response in head and neck cancer - PubMed
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- #head and neck cancer
- #cell-free DNA
- #immunotherapy response
- The study introduces the regional motif diversity score (rMDS), a fragmentomic metric that quantifies entropy of cfDNA 5'-end motifs across genomic regions, to predict immunotherapy response in head and neck squamous cell carcinoma (HNSCC).
- rMDS robustly distinguished responders from non-responders in a prospective trial, outperforming established biomarkers like PD-L1 expression and tumor fraction, with high accuracy (AUC 0.89-0.99) in validation settings.
- Longitudinal changes in rMDS localized to genomic regions enriched for immune-, lectin-, and keratinization-related genes, and clustered at telomere-proximal loci, linking telomere biology to cfDNA fragmentation during treatment.
- Predicted responders based on rMDS showed improved disease-free survival (log-rank P=0.035; HR 2.67), supporting its potential as a clinically actionable biomarker for immunotherapy response in HNSCC.