HPV16 genomic status stratifies risk of disease recurrence in oropharyngeal squamous cell carcinoma.
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- Record sourced from PubMed, PMID 42456052.
- Also identified by DOI 10.1158/1078-0432.CCR-26-0732.
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Abstract
A subset of patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma develops disease recurrence despite generally favorable outcomes. Reliable biomarkers for risk stratification remain lacking. We investigated whether comprehensive viral genomic profiling refines prognostic classification. Tumor samples from 100 patients with p16-positive and human papillomavirus DNA-positive oropharyngeal squamous cell carcinoma enrolled in two independent cohorts were analyzed using targeted viral capture sequencing. Viral genotype, sublineage, single-nucleotide variation, viral-host integration sites, viral structural variants, clonality, and viral copy number were characterized. Associations with cumulative incidence of progression, progression-free survival and overall survival were assessed at 60 months. Human papillomavirus 16 was detected in 94 tumors, of which 83 belonged to the HPV16_A1 sublineage. Within this sublineage, 20 tumors harbored strictly episomal viral genomes, whereas 63 exhibited integration and/or viral structural variants. No progression events occurred in the strictly episomal HPV16_A1 subgroup, while 12 occurred among tumors HPV16_A1 with integration and/or structural variant. At 60 months, no progression events were observed in strictly episomal HPV16_A1 tumors, compared with a 23.1% cumulative incidence of progression in HPV16_A1 tumors with integration and/or structural variant. Previously reported high-risk single-nucleotide variants and a novel upstream regulatory region variant were associated with worse progression-free survival. Integration sites were enriched in open chromatin and promoter regions and clustered within viral E2 and E4 genes. Within human papillomavirus 16 A1 tumors, viral genomic architecture defines clinically distinct subgroups. Strictly episomal (WT) genomes identify a low-risk population, whereas integration and structural variants characterize higher-risk disease.