Background
Human papillomavirus (HPV)–driven head and neck cancers (HNC) are commonly identified using molecular biomarkers such as p16 immunohistochemistry, HPV DNA/RNA detection, and HPV16 E6 serology. While these biomarkers are largely concordant, a subset of tumors display discordant biomarker profiles, complicating diagnosis and risk stratification. The biological basis for this discordance is poorly understood. HPV genome variation (including viral lineage, sequence variation, and viral–host integration state) may influence tumor biology and biomarker performance. However, systematic evaluation of viral genomic features in relation to established HPV biomarkers and clinical outcomes has been limited. The VOYAGER consortium provides a valuable resource to address these questions through tumor sequencing data with full HPV16/18 genome coverage combined with harmonized biomarker and clinical data.
 
Objectives
The project aims to (i) reconstruct HPV viral genomes using lineage-aware approaches and identify novel genomic features, (ii) investigate how HPV characteristics affect HPV biomarker performance, and (iii) evaluate their clinical significance, e.g. impact on patient outcomes.
 
Methods
This is a planned and ongoing study using large-scale genomic and clinical data generated in the VOYAGER (human papillomaVirus, Oral and oropharYngeal cAncer GEnomic Research) program. VOYAGER is a consortium of five large studies on HNC in North America and Europe encompassing more than 10,000 participants, with DNA sequencing performed for 999 tumors. A bioinformatic pipeline for HPV genome assembly and sublineage classification will be established to accurately distinguish HPV variants. HPV features (including sublineage, viral load, viral diversity, number and location of integration sites) will be correlated with HPV biomarker data to evaluate the influence of viral genomic features on diagnostic performance. By analyzing cases of discordance between HPV biomarkers, this study will assess whether the discordance reflects underlying HPV genome variation, and whether this may identify clinically meaningful subgroups that are currently overlooked in standard HPV classification.
 
Results
As the project is currently at an early stage, results are not yet available at time of abstract submission.
 
Implications for practice or policy
The project will establish a robust framework for integrating HPV viral genomics with diagnostic biomarker data in HNC. Results from this study will provide insights into viral heterogeneity in HPV-driven HNC to support interpretation of HPV diagnostics and inform future risk stratification strategies.