Association of Liquid Biopsy Biomarkers with Survival Outcomes in Oropharyngeal Squamous Cell Carcinoma

Abstract

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is increasingly associated with humanpapillomavirus (HPV) infection and often presents at advanced stages, contributing to substantial morbidity and mortality. Liquid biopsy offers a promising, non-invasive approach for cancer detection and monitoring; however, the prognostic significance of many reported biomarkers remains unclear. Objective: To systematically assess the prognostic relevance of liquid biopsy biomarkers in OPSCC using multi- omic data from The Cancer Genome Atlas (TCGA), and to evaluate their potential to complement established molecular markers. Methods: A systematic literature search identified diagnostic liquid-based biomarkers across molecular modalities, including DNA mutations, DNA methylation, gene expression, and miRNA expression. Biomarkers were mapped to TCGA OPSCC datasets, and their associations with overall survival were evaluated using univariate and multivariate Cox proportional hazards models, adjusting for HPV status, CDKN2A expression, and TP53/NOTCH1 mutations. Pathway enrichment analysis was conducted to explore biological relevance. Results: From 1,544 curated gene symbols corresponding to liquid-based biomarkers, 524 were significantly associated with worse overall survival in OPSCC (p < 0.05). DNA methylation markers near MIR21, VMP1, and KCNC1 exhibited the strongest prognostic performance (C-index > 0.69). Pathway enrichment analysis revealed that prognostic biomarkers were involved in key processes including extracellular matrix (ECM) organization, epithelial-mesenchymal transition (EMT), and oncogenic signaling via MAPK, Notch, and PI3K pathways. Importantly, 1,180 biomarkers provided independent prognostic value beyond established markers. Conclusion: This study demonstrates that a subset of liquid-based biomarkers holds strong prognostic value in OPSCC, independent of established molecular indicators. Integrating multi-omic biomarkers into liquid biopsy strategies may enhance risk stratification, support personalized treatment decisions, and improve monitoring of disease progression in OPSCC. Prospective validation is warranted to translate these findings into clinical practice.