HPV and head and neck cancers: Towards early diagnosis and prevention

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with an increasing trend of its incidence. Alcohol consumption, smoking, and viral infections, such as the mucosal high-risk (HR) human papillomaviruses (HPVs) are major risk factors for HNSCC development. In particular, HR HPVs are mainly associated with a subset of oropharyngeal squamous cell carcinoma (OPSCC), while other head and neck sites are marginally affected by HPV infection. HPV16 is the most frequently HR HPV type associated with HNSCC. In contrast to the cervix, no screening programs or identifiable pre-malignant lesions have been characterized for HPV-related HNSCC. Therefore, identification of general diagnostic algorithms and HPV biomarkers that could facilitate the early diagnosis, disease evolution and recurrence for HPV-driven HNSCCs are urgently needed. We herein review the role of HPV in HNSCC with a focus on epidemiology, biology, applied diagnostic algorithms and available biomarkers in body fluids as early diagnostic tools in HPV-driven HNSCCs.

Keywords: Biomarkers; Cancer of the oropharynx; Diagnostic algorithm; Early diagnosis; HNC; HNSCC; HPV; Liquid biopsy.

Fig. 1

E6 and E7 HPV oncoproteins degrade p53 and pRb, respectively. A. E6-induced p53 degradation through the formation of a ternary complex. Binding of E6 to p53 induces its ubiquitylation and proteasomal-mediated degradation, via the ubiquitin E3 ligase E6-associated protein (E6AP). B. Degradation of pRb, overexpression of CDKs and inactivation of CDK inhibitors all contribute to E2F overexpression and uncontrolled cell-cycle progression in cancers. Whereas hypo-phosphorylation of pRb prevents effects of E2F and renders cells quiescent, CDK/D-cyclin association causes its phosphorylation and release from E2F. Binding of E7 also causes release of E2F through ubiquitylation and proteasomal degradation of pRb [[163], [164], [165], [166], [167]]. Created withBioRender.com.

Fig. 2

Diagnostic assays and viral biomarkers in HPV-related HNSCCs identification Concepts for possible diagnostic algorithms to identify HPV-driven HNSCC using a combination of direct (HPVDNA + E6*I mRNA/E6-E7 mRNA) and surrogate cellular markers (p16^INK4a) of oncogenic HPV infection in fresh and FFPE tissues (lower panel). HPV-biomarkers in body fluids used in combination with diagnostic algorithm for early diagnosis and follow-up of HNSCCs (upper panel).