Microbiome factors in HPV-driven carcinogenesis and cancers

Human papillomavirus (HPV) infections account for over 600,000 new cancer cases every year [1]. HPV is implicated in approximately 70% of oropharyngeal cancers (OPCs), 90% of anal cancers, and virtually all cases of invasive cervical cancer (ICC) in the U.S [2]. HPV carcinogenesis is mediated by its E6 and E7 oncoproteins, which force differentiating epithelial cells to re-enter the cell cycle to grow and increase viral production [3]. Although most HPV infections resolve over time, persistent infection can cause catastrophic cell-cycle instability and eventually lead to invasive cancer [2]. Nevertheless, HPV presence alone is insufficient for cancer formation. Factors unique to the individual mucosal sites such as epithelial surface integrity, mucosal secretions, immune regulation, and the local microbiota likely play a role in HPV persistence and progression to cancer [2-4]. Dysbiosis of the microbiome can have profound effects on overall health and has recently been linked to cancer progression and treatment responses [5]. Methodological advances in microbiome sequencing and analysis have enabled these recent sweeping advances in knowledge. In particular, 16S ribosomal RNA (rRNA) amplicon sequencing is frequently used. This cost-effective method sequences specific hypervariable regions of the 16S rRNA gene and clusters the identified bacteria into operational taxonomic units (OTUs) that can quantify diversity metrics and relative abundances, as well as provide genus-level identification [6]. However, 16S rRNA subregion sequencing has inherent disadvantages, including the inability to provide species-level identification and metagenomic functionality. These deficiencies could be overcome with whole-genome shotgun (WGS) sequencing. WGS deciphers broad regions of entire microbial genomes with significantly more sequencing depth but at a greater cost and use of bioinformatics resources than 16S rRNA analysis [7]. Despite these barriers, notable advantages include enhanced species-level identification and accuracy, improved microbial diversity detection, insight into genome functionality and structure, and the ability to identify nonbacterial microorganisms such as viruses and fungi, which are also critical parts of a tissue's microbiome [7]. Used in conjunction, these complementary methods may provide further clues to understanding the microbiome's role in HPV carcinogenesis. HPV cancers may be uniquely affected by the microbiome since these solid tumors arise in the mucosa of the orogenital tract, which each have unique and diverse microbiomes. Insights into the potential influence of the microbiome on viral persistence, immune response, host-mucosal environment, and cancer treatments for HPV-related cancers are just beginning to emerge. In this review, we will discuss how the microbiome may play a pivotal role in the formation of HPV-driven cancers.