Human Papillomavirus (HPV) Viral Proteins Substitute for the Impact of Somatic Mutations by Affecting Cancer-Related Genes: Meta-analysis and Perspectives

Abstract

Purpose: Although a strong association between human papillomavirus (HPV) and a variety of cancers has long been established, infection by HPV alone has been shown to be insufficient for the induction of cancer, with a large number of HPV infections regressing without causing cancer. Additionally, HPV-negative cases have worse prognosis rates than HPV-positive ones across a multitude of cancer types. The reasons behind these phenomena are poorly understood. We try to explain it. Methods: In this meta-analysis study, we first compared the mutation sets of HPV-positive and HPV-negative cancers using data from the Cancer Genome Atlas (TCGA) and from open published sources. Then, focusing on the genes that are exclusively mutated in HPV-negative head and neck cancer, we used KEGG pathways and reviewed literature to investigate how HPV can mimic the effects of mutations in those genes and thereby trigger carcinogenesis despite the absence of those mutations. Results: Using TCGA mutation frequencies of significantly mutated genes stratified by HPV status, we extracted 17 genes exclusively mutated in HPV-negative cancers and detailed the HPV infection mechanisms that are largely able to mimic the effects of mutations in 13 of these genes. Through our literature searches and pathway analyses, we also presented antitumor effects caused by HPV infection that reduce carcinogenic efficiency and could contribute to the prognosis difference. Conclusion: Our findings confirm that HPV infection substitutes for some, but not all, somatic driver mutations required for the induction of cancer by mimicking the effects of those mutations through various virus–host interaction mechanisms, thereby accelerating the cancer-related pathways.