Unveiling the Association between HPV and Pan-Cancers: A Bidirectional Two-Sample Mendelian Randomization Study.

Area of Science:

• Oncology
• Virology
• Genetics

Background:

• Growing research links human papillomavirus (HPV) infection to various cancers.
• Existing evidence primarily stems from retrospective studies, limiting causal inference.
• Mendelian randomization (MR) offers a robust approach to investigate causal relationships, overcoming limitations of observational studies.

Purpose of the Study:

• To establish causal relationships between specific human papillomavirus (HPV) types and 12 site-specific cancers using a bidirectional two-sample Mendelian randomization (MR) design.
• To explore the potential role of HPV in cancer development beyond cervical cancer.
• To investigate the impact of HPV on the tumor-immune microenvironment in select cancers.

Main Methods:

• Employed a bidirectional two-sample MR design utilizing single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) as instrumental variables for HPV exposure.
• Conducted sensitivity analyses including MR-Egger's intercept, MR-PRESSO, Cochran's Q test, and leave-one-out analysis to ensure result validity.
• Performed immune infiltration analyses using HPVTIMER in head and neck squamous cell carcinoma (HNSCC), oropharyngeal squamous cell carcinoma (OPSCC), and vulval squamous cell carcinoma (VSCC) to assess the tumor-immune microenvironment.

Main Results:

• HPV16 was identified as a risk factor for bladder, colorectal, and breast cancers.
• HPV18 was identified as a risk factor for prostate, ovarian, lung, and breast cancers.
• HPV16 demonstrated a potential protective effect against prostate, anal, lung, and oropharyngeal cancers, while HPV18 showed a similar effect for vaginal cancer.

Conclusions:

• HPV infection may influence the tumor-immune microenvironment, potentially inhibiting the development of certain cancers.
• The findings offer novel perspectives on cancer development mechanisms.
• Further research is warranted to validate these causal associations and explore underlying biological pathways.