Introduction: More and more studies have focused on the associations between human papillomavirus (HPV) infection and pan-cancers. However, current evidence is largely based on retrospective studies, which are susceptible to confounding factors and do not enable the establishment of causal relationships. Methods: A bidirectional two-sample Mendelian randomization (MR) design was employed to thoroughly evaluate the causal relationships between HPV and 12 site-specific cancers except cervical cancer. Single nucleoside polymers (SNPs) with strong evidence from genome-wide association studies (GWAS) were selected from HPV exposure datasets and used as instrumental variables (IVs) in this study. For the MR analysis results, MR-Egger’s intercept P test, MR-PRESSO global test, Cochran’s Q test and a leave-one-out test were applied for sensitivity analysis. Using HPVTIMER, we also performed immune infiltration analyses in head and neck squamous cell carcinoma (HNSCC), oropharyngeal squamous cell carcinoma (OPSCC) and vulval squamous cell carcinoma (VSCC) to evaluate the tumor-immune microenvironment. Results: Based on the evidence of MR analysis, our study conclusively identified HPV16 as a risk factor implicated in the development of bladder cancer, colorectal cancer, and breast cancer, while HPV18 was identified as a risk factor for prostate cancer, ovarian cancer, lung cancer and breast cancer. The MR results also showed that HPV16 may be a protective factor for prostate cancer, anal cancer, lung cancer and oropharyngeal cancer, while HPV18 may be a protective factor for vaginal cancer. Conclusion: An HPV infection may modulate the immune microenvironment and therefore has a potential inhibitory effect on the development of certain cancers. These conclusions provided new insights into the potential mechanisms of carcinogenesis and needed further research for validation.
引言：越来越多的研究关注人乳头瘤病毒（HPV）感染与泛癌之间的关联。然而，现有证据主要基于回顾性研究，易受混杂因素影响，且无法确立因果关系。方法：本研究采用双向双样本孟德尔随机化（MR）设计，全面评估HPV与除宫颈癌外的12种特定部位癌症之间的因果关系。我们从HPV暴露数据集中选取了具有全基因组关联研究（GWAS）强证据的单核苷酸多态性（SNPs）作为工具变量（IVs）。针对MR分析结果，我们应用MR-Egger截距P检验、MR-PRESSO全局检验、Cochran's Q检验及留一法检验进行敏感性分析。同时，利用HPVTIMER工具对头颈部鳞状细胞癌（HNSCC）、口咽鳞状细胞癌（OPSCC）和外阴鳞状细胞癌（VSCC）进行免疫浸润分析，以评估肿瘤免疫微环境。结果：基于MR分析证据，本研究明确发现HPV16是膀胱癌、结直肠癌和乳腺癌发展的风险因素，而HPV18被确定为前列腺癌、卵巢癌、肺癌和乳腺癌的风险因素。MR结果同时显示，HPV16可能是前列腺癌、肛门癌、肺癌和口咽癌的保护因素，而HPV18可能对阴道癌具有保护作用。结论：HPV感染可能通过调节免疫微环境，从而对某些癌症的发展产生潜在抑制作用。这些结论为癌症发生的潜在机制提供了新见解，但需进一步研究验证。
肿瘤(癌症)患者之家