Mutations in High-Risk Human Papillomavirus (HPV) Genotypes: Implications for Genetic Variability and Its Relationship with Cervical Cancer

Human papillomavirus (HPV) remains the principal etiological agent of cervical cancer, accounting for more than 95% of cases worldwide. Although the carcinogenic role of high-risk genotypes such as HPV-16 and HPV-18 has been extensively established, growing evidence suggests that genetic variability within individual genotypes may contribute to differences in viral persistence, oncogenic potential, immune evasion, and clinical outcomes. This scoping review aimed to synthesize current evidence regarding intratype mutations, viral lineages, and sublineages of high-risk HPV genotypes and to examine their implications for cervical carcinogenesis, vaccine effectiveness, and molecular diagnosis. A literature search was conducted following the PRISMA-ScR framework using PubMed, Scopus, Web of Science, and supplementary searches and citation tracking. Fifty-four studies met the eligibility criteria and were included in the qualitative synthesis. The available evidence suggests considerable genomic heterogeneity among high-risk HPV genotypes, although the strength of the reported associations varies substantially across studies. Several observational studies have suggested that non-European HPV-16 lineages, particularly lineage D sublineages, may be associated with an increased risk of cervical cancer. Mutations affecting the E6, E7, and long control region (LCR) have been reported to be associated with altered viral transcriptional activity, persistence, and oncogenic potential. Genetic variability may influence molecular diagnostic performance and potentially affect vaccine-induced immune responses. However, most reported associations are supported by a limited number of observational studies and should therefore be interpreted with caution. Overall, the available evidence supports the integration of genomic surveillance into HPV prevention and control strategies while highlighting the need for additional high-quality studies to clarify the clinical significance of HPV intratype genomic diversity.