Abstract
BACKGROUND: Human papillomavirus (HPV), a known oncogenic virus in cervical and anal cancers, has also been detected in colorectal tissues. However, evidence regarding its association with colorectal cancer (CRC) remains inconsistent. We conducted an updated systematic review and meta-analysis to clarify this relationship. METHODS: Following PRISMA 2020 guidelines, we systematically searched PubMed, Embase, Web of Science, and Cochrane Library through May 2025 for observational studies (case-control and cross-sectional) assessing HPV prevalence in CRC patients versus controls. Data extraction was performed in duplicate. Pooled odds ratios (ORs) were estimated using random-effects models with logit transformation. Subgroup analyses and meta-regression examined the effects of geographic region, HPV genotype, detection method, and sample type. Risk of bias was assessed using the Newcastle-Ottawa Scale. FINDINGS: Twenty case-control studies encompassing 1424 CRC cases and 1363 controls were included. The pooled OR for the association between HPV infection and CRC was 2.39 (95% CI: 1.69-3.09), with no significant heterogeneity ( I2 = 0%). Associations were strongest in Asian studies (OR = 3.73) and in those using formalin-fixed paraffin-embedded (FFPE) tissues (OR = 3.56). Studies targeting HPV16 alone yielded higher effect sizes than those evaluating mixed or unspecified genotypes. Meta-regression confirmed region and genotype group as significant effect modifiers. Leave-one-out sensitivity analysis confirmed robustness. Egger's test indicated marginal small-study bias ( P = 0.074), but funnel plot symmetry suggested no serious publication bias. CONCLUSION: This meta-analysis confirms a significant link between HPV infection and colorectal cancer, suggesting HPV may play a broader oncogenic role beyond the anogenital tract. The findings highlight the need for genotype-aware, region-specific screening strategies, and support incorporating viral profiling into CRC prevention efforts, especially in underserved populations.