The association between human papillomavirus and bladder cancer: Evidence from meta-analysis and two-sample mendelian randomization

Abstract

Introduction: Bladder cancer (BCa) is the 10th most common type of cancer worldwide, and human papillomavirus (HPV) is the most common sexually transmitted infection. However, the relationship between HPV infection and the risk of BCa is still controversial and inconclusive.

Methods: This systematic review and meta-analysis were conducted following the PRISMA 2020 reporting guideline. This study searched four bibliographic databases with no language limitation. The databases included PubMed (Medline), EMBASE, Cochrane Library, and Web of Science. Studies evaluating the interaction between HPV infection and the risk of BCa from inception through May 21, 2022, were identified and used in this study. This study estimated the overall and type-specific HPV prevalence and 95% confidence intervals (95% CI) using Random Effects models and Fixed Effects models. In addition, this study also calculated the pooled odds ratio and pooled risk ratio with 95% CI to assess the effect of HPV infection on the risk and prognosis of bladder cancer. Two-sample mendelian randomization (MR) study using genetic variants associated with HPV E7 protein as instrumental variables were also conducted.

Results: This study retrieved 80 articles from the four bibliographic databases. Of the total, 27 were case-control studies, and 53 were cross-sectional studies. The results showed that the prevalence of HPV was 16% (95% CI: 11%-21%) among the BCa patients, most of which were HPV-16 (5.99% [95% CI: 3.03%-9.69%]) and HPV-18 (3.68% [95% CI: 1.72%-6.16%]) subtypes. However, the study found that the prevalence varied by region, detection method, BCa histological type, and sample source. A significantly increased risk of BCa was shown for the positivity of overall HPV (odds ratio [OR], 3.35 [95% CI: 1.75-6.43]), which was also influenced by study region, detection method, histological type, and sample source. In addition, the study found that HPV infection was significantly associated with the progression of BCa (RR, 1.73 [95% CI: 1.39-2.15]). The two-sample MR analysis found that both HPV 16 and 18 E7 protein exposure increased the risk of BCa (HPV 16 E7 protein: IVW OR per unit increase in protein level = 1.0004 [95% CI: 1.0002-1.0006]; p = 0.0011; HPV 18 E7 protein: IVW OR per unit increase in protein level = 1.0003 [95% CI: 1.0001-1.0005]; p = 0.0089).

Conclusion: In conclusion, HPV may play a role in bladder carcinogenesis and contribute to a worse prognosis for patients with BCa. Therefore, it is necessary for people, especially men, to get vaccinated for HPV vaccination to prevent bladder cancer.

Keywords: HPV prevalence; bladder cancer; human papillomavirus; mendelian randomization; meta-analysis.

Figure 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flowchart for study selection for the systematic review on HPV infection and the risk of bladder cancer. HPV, human papillomavirus.

Figure 2

Forest plot for the prevalence of HPV in bladder cancer cases. Pooled prevalence and 95% confidence intervals of HPV infection, using a random‐effect model. HPV, human papillomavirus.

Figure 3

Subgroup analyses for HPV prevalence in bladder cancer cases stratified by continent, country, detection method, histological type, and study type. CI, confidence interval; ISH, in situ hybridization; No., number; PCR, polymerase chain reaction; SCC, squamous cell carcinoma; TCC, transitional cell carcinoma.

Figure 4

Subgroup analyses for HPV prevalence in bladder cancer cases stratified by HPV subtypes. CI, confidence interval; HPV, human papilloma virus.

Figure 5

Forest plot for the association between HPV infection and bladder cancer risk. Pooled odds ratios and 95% confidence intervals of bladder cancer risk associated with HPV infection, using the random‐effects model. HPV, human papilloma virus.

Figure 6

Subgroup analyses for OR of bladder cancer stratified by continent, detection method, histological type and sample source.

Figure 7

Forest plot for the association between HPV infection and bladder cancer prognosis. Pooled relative risks and 95% confidence interval for the prognosis of bladder cancer associated with HPV infection, using the common‐effects model. HPV, human papilloma virus.

Figure 8

Subgroup analyses for RR of bladder cancer progression stratified by continent, outcomes, detection method, histological type, and sample source.

Figure 9

The 2‐sample Mendelian randomization (MR) analysis. (A) Forest plot for the 2‐sample MR analysis representing the causal estimate of HPV‐16 E7 protein for bladder cancer. Circles alongside each SNP represent the causal estimate of each instrumental variable separately, and the lowest two circles show multiple‐instrument MR analysis using Egger regression and inverse‐variance weighted methods. Horizontal lines denote 95% CIs. IVW, inverse variance weighted; SD, standard deviation. (B) Scatter plot for causal effects of HPV‐16 E7 protein on bladder cancer. Slope of the straight line indicates the magnitude of causal association. IVW indicates inverse‐variance weighted; MR, Mendelian randomization. (C) Funnel plots for overall heterogeneity of MR estimates for the effect of HPV 16 E7 protein on bladder cancer. IVW, inverse‐variance weighted. (D) Leave‐one‐out sensitivity analysis of bladder cancer to investigate the possibility of causal association driven by a particular SNP. Each black point represents an inverse variance weighted method for estimating the causal effect of HPV 16 E7 protein on bladder cancer, excluding that particular instrumental variable from the analysis. Redpoint represents the estimate using all instrumental variables. Horizontal lines denote 95% confidence intervals. OR, odds ratio; SD, standard deviation. (E) Meta‐analysis for results of MR studies using different bladder cancer datasets including finn‐b‐C3_BLADDER_EXALLC, finn‐b‐CD2_BENIGN_BLADDER_EXALLC, ieu‐b‐4874, ukb‐d‐C67.