Human papillomavirus 16 genomic variation in head and neck cancer: a systematic review with structural and functional annotation

Human papillomavirus type 16 (HPV16)-positive head and neck cancer (HNC) is generally associated with a more favourable prognosis than HPV-negative disease. However, emerging evidence suggests that specific HPV16 genomic variants may be associated with poorer clinical outcomes. We therefore conducted a systematic review of HPV16 single nucleotide polymorphisms (SNPs) reported in HNC and mapped selected variants to viral genomic and protein regions to assess their potential relevance. We searched four major databases (PubMed, Embase, Scopus, and Web of Science) for studies reporting HPV16 SNPs in HNC. Most studies focused on either E6 or E7, while only a few studies examined the entire HPV16 sequence. These SNPs were extracted and mapped to the HPV16 genome, while structural and functional characteristics were assessed using UniProt and the RCSB Protein Data Bank. Fourteen studies were analysed, identifying 30 SNPs in E6 and seven in E7. Structural mapping suggested that core HPV16 oncogenic motifs remain highly conserved, while recurrent variants tend to occur in mutationally permissive regions, such as the E6 interdomain linker. Only one study reported associations between HPV16 variants and poorer patient survival within the upstream regulatory region. However, these findings require independent validation before any clinical relevance can be established. The comprehensive mapping of HPV16 SNPs in HNC provides an important grounding for understanding how these SNPs may be associated with disease progression and patient outcomes. Although many of the identified SNPs are within important HPV16 regions, their associations with disease progression remain unclear. Further studies are required to determine which variants are associated with patient outcomes. A more comprehensive understanding of HPV16 genomic variation and its relevance could provide broader clinical insights across HPV16-associated cancers.