Risk of Human Papillomavirus Infection in Cancer-Prone Individuals: What We Know

Abstract

Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have been intensely studied in laboratory models and humans. What remains largely unknown are host tissue and immune-related factors that determine an individual’s susceptibility to infection and/or carcinogenesis. Such susceptibility factors could serve to identify those at greatest risk and spark individually tailored HPV and SCC prevention efforts. Fanconi anemia (FA) is an inherited DNA repair disorder that is in part characterized by extreme susceptibility to SCCs. An increased prevalence of HPV has been reported in affected individuals, and molecular and functional connections between FA, SCC, and HPV were established in laboratory models. However, the presence of HPV in some human FA tumors is controversial, and the extent of the etiological connections remains to be established. Herein, we discuss cellular, immunological, and phenotypic features of FA, placed into the context of HPV pathogenesis. The goal is to highlight this orphan disease as a unique model system to uncover host genetic and molecular HPV features, as well as SCC susceptibility factors.

More than just oncogenes: mechanisms of tumorigenesis by human viruses

“…These patients harbor mutations in genes that control genomic stability, and frequently develop oral cancers and squamous cell carcinomas at sites consistent with high-risk HPV infections. Most studies indicate, however, that these cancers are HPV-negative [112]. It is thus conceivable that HPVs may initially trigger carcinogenesis, but that because of the high rate of mutations in Fanconi Anemia patients, the oncogenic pathways initially targeted by E6 and E7 may be rapidly inactivated by mutation.…”

Limited detection of human polyomaviruses in Fanconi anemia related squamous cell carcinoma

“…Seventeen percent of the FAHNSCC showed weak reactivity using pan-PyV antibodies. The weak positivity of some of the specimens may suggest a hit-and-run mechanism for carcinogenesis similar to a scenario proposed for HPV in FA [20]. This scenario was based on key studies by the Lambert laboratory where sustained SCC growth in Fancd2 knockout mice occurred even in the absence of the viral E7 oncogene, perhaps due to virally induced DNA damage accumulation and rapid selection for oncogene-independent tumor growth [30].…”

“…HPV replication is limited by the FA pathway and FANCA or FANCD2 deficiency can lead to HPV-associated hyperplastic growth in 3D engineered epidermis [12]. Although several groups have detected the presence of HPV in SCC [13–15], as well as seropositivity and increased prevalence of oral HPV in FA patients [16], a causal association for the high-risk HPV types 16/18 in FA HNSCC remains controversial [17–20].…”

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

“…Although the role of HPV in FA-related head and neck tumors remains controversial [ 153 , 154 ], different hypotheses have emerged about HPV susceptibility or persistence. On the one hand, the immune impairment associated with FA could play a role [ 155 ], and the prolonged state of immunosuppression and late immune reconstitution may predispose FA patients to viral infections and the consequent cellular changes involved in tumorigenesis. On the other hand, defects in virophagy cannot be ignored.…”