DNA Methylation Triage after High-Risk Human Papillomavirus Detection: A Critical Narrative Review of Oncogenic Risk Stratification and Precision Cervical Cancer Prevention in West Africa

Abstract

High-risk human papillomavirus (hrHPV) DNA testing has transformed cervical cancer screening because it detects infection with substantially greater sensitivity than morphology-based approaches. Its principal limitation is biological: most hrHPV infections do not progress to cancer, so a positive result identifies exposure and persistence risk rather than the molecular state of transformation. DNA methylation testing has emerged as a candidate reflex triage strategy that measures host-cell or viral epigenetic changes associated with advanced transforming lesions and invasive cancer. This critical narrative review evaluates the biological rationale, clinical performance, self-sampling compatibility, longitudinal evidence, and implementation requirements of methylation-based triage, with particular emphasis on West Africa and on women living with human immunodeficiency virus. Literature published principally from 2010 through 30 June 2026 was identified through international and African scholarly sources, supplemented by citation searching and authoritative guidelines. Across heterogeneous assays, methylation generally rises with lesion severity and provides clinically relevant discrimination among hrHPV-positive women. The most mature evidence supports host panels such as FAM19A4/miR124-2 and ASCL1/LHX8, and combined host-viral classifiers such as S5; other panels remain promising but less externally validated. A major translational advantage is the possibility of reflex testing on the same molecular specimen, including self-collected material, thereby reducing dependence on cytology and repeated clinic attendance. Yet assay-specific thresholds, pre-analytical variation, age effects, heterogeneous endpoints, and geographical concentration of validation studies limit direct transfer to West African programmes. Regional studies demonstrate substantial hrHPV prevalence, diverse genotype distributions, practical feasibility of self-sampling and hub-and-spoke molecular services, and a particular need for efficient triage among women living with human immunodeficiency virus. Direct Nigerian methylomic evidence strengthens biological plausibility but is not yet equivalent to prospective clinical triage validation. Methylation testing is therefore best regarded as a precision-oriented triage technology requiring locally calibrated prospective validation, clinical-utility evaluation, affordability analysis, and integration with assured treatment pathways before routine implementation in West Africa.