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Background There is an intense research interest on the fragmentomics analysis of plasma DNA in the field of liquid biopsy. Recent studies revealed the fragmentomics signatures of plasma Epstein-Barr virus DNA that were associated with nasopharyngeal carcinoma (NPC). Such analysis demonstrated potentials to enhance the performance of NPC diagnostics.Methods In a prospective cohort of NPC patients receiving induction immunotherapy (pembrolizumab) and concurrent chemoirradiation, we analysed the plasma EBV DNA with targeted sequencing at different timepoints of the treatment course. Specifically, the fragment size, end motif and fragmentation-based methylation analysis (FRAGMA) profiles of plasma EBV DNA were studied.Results The dynamics of plasma EBV DNA levels, quantified through targeted sequencing, were analysed in the patient cohort. We observed serial changes in EBV DNA levels during treatment, which were then evaluated for correlation with clinical responses and survival outcomes. Furthermore, we examined the fragmentomics profile of plasma DNA, identifying notable changes in fragment size distribution and FRAGMA patterns over the course of therapy. These fragmentomics alterations showed potential as predictive biomarkers for treatment response and disease progression.Conclusions Serial analysis of plasma EBV DNA by targeted sequencing could be further explored in the management of patients receiving immunotherapy.Acknowledgements This work was supported by the Innovation and Technology Fund under the InnoHK Initiative, a major initiative of the Hong Kong Special Administrative Region Government, and the Research Grants Council of the Hong Kong SAR Government under the NSFC/RGC Joint Research Scheme (N_CUHK495/22).Ethics Approval The study was approved by the Joint Chinese University of Hong Kong – Hospital Authority New Territories East Cluster Clinical Research Ethics Committee and in compliance of the Declaration of Helsinki.Consent All the participants provided written informed consent for the study.