Lineages and sublineages of high-risk HPV types associated with cervical cancer and precancer: a systematic review and meta-analysis

Abstract

BACKGROUND Infection with high-risk types of the human papillomavirus (hrHPV) is known to cause cervical cancer. Cervical cancer risk varies greatly by genotype, which is therefore used in screening algorithms. A significant amount of research has also focused on the differential pathogenicity of hrHPV subtypes called lineages and sublineages (resp. 1.0-10% and 0.5-1.0% genetic difference), albeit with inconclusive and contradictory results. Therefore, the topic is systematically reviewed for the first time to determine whether the clinical use of (sub)lineage detection is supported. METHODS Three databases for health sciences (PubMed, Web of Science, and Scopus) were searched for relevant papers. Meta-analysis was performed for HPV16 positive cancers and controls using random effects models. RESULTS The search yielded 1,535 records and 93 papers were included after the selection process. Although some trends in disease association were detected, 46 studies did not find significant differences between (sub)lineages in cases and controls. Additionally, the reports are heterogeneous in terms of study design and often characterized by a small sample size. The meta-analysis found odds ratios of 2.2 [95% CI: 1.49-3.15] for HPV16 A4, 2.1 [95% CI: 1.25-3.40] for HPV16 D and 0.48 [95% CI: 0.33-0.68] for HPV16 A1-3 with significant heterogeneity (38-77%). CONCLUSION This systematic review and meta-analysis provides an overview of the hrHPV (sub)lineages and association with cervical disease. Although some (sub)lineages marginally correlate with cervical malignancy, there is great variability. Unlike genotyping, this study demonstrates insufficient association between hrHPV (sub)lineages and cervical malignancy for clinical use to date.