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.

Role of human papillomavirus and associated viruses in bladder cancer: An updated review

“…27,57 A recent meta-analysis has demonstrated that HPV may be involved in the development and progression of BC, as well as contribute to the unfavorable prognosis of patients. 41 Moreover, a study in Iran revealed that HPV positivity was as high as 71.4% in BC tissues and 33.6% in urine samples, which exhibited a significant correlation with both the grade and stage of cancer. 57 However, another meta-analysis from Iran indicated a lack of notable correlation between HPV infection and BC.…”

“…Recently, extensive evidence has demonstrated a strong correlation between HPV and BC, with the virus significantly affecting the development and prognosis of BC (Table 2). 40 In their study, Sun et al 41 reported that HPV infection was correlated with a significantly increased risk and a worse prognosis for BC. Moreover, HPV infection causes chronic inflammation, which induces the excessive release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from epithelial cells, leading to DNA damage.…”

“…42 Several studies have assessed the effect of HPV infection on the bladder epithelium owing to the anatomical proximity of the bladder and genital organs and sexual transmission. 26,41 Moreover, HPV DNA has been detected in urine and washing specimens of patients with BC as well as in BC tissues. 43,44 In addition, high-risk HPV infection is positively correlated with tumor progression, which was attributed to p53 mutation.…”

“…Accumulated damage accelerates DNA mutations, ultimately fostering the initiation and progression of carcinogenesis 42 . Several studies have assessed the effect of HPV infection on the bladder epithelium owing to the anatomical proximity of the bladder and genital organs and sexual transmission 26,41 . Moreover, HPV DNA has been detected in urine and washing specimens of patients with BC as well as in BC tissues 43,44 .…”

Genetic and epigenetic characteristics of non-muscle invasive and muscle invasive bladder cancer in patients infected by human papillomavirus: literature review

“…Вместе с тем появились публикации, указывающие на влияние ВПЧ на течение РМП. Так, результаты опубликованного в 2022 г. метаанализа демонстрируют ухудшение прогноза течения РМП у ВПЧ-инфицированных пациентов [15], в другой публикации указана определенная этиологическая роль ВПЧ-инфицирования в развитии РМП [16]. В определенной степени сходное мнение высказывает другая группа исследователей [17].…”