Virology and molecular pathogenesis of HPV (human papillomavirus)-associated oropharyngeal squamous cell carcinoma

Abstract

The current literature fully supports HPV (human papillomavirus)-associated OPSCC (oropharyngeal squamous cell carcinoma) as a unique clinical entity. It affects an unambiguous patient population with defined risk factors, has a genetic expression pattern more similar to cervical squamous cell carcinoma than non-HPV-associated HNSCC (head and neck squamous cell carcinoma), and may warrant divergent clinical management compared with HNSCC associated with traditional risk factors. However, a detailed understanding of the molecular mechanisms driving these differences and the ability to exploit this knowledge to improve clinical management of OPSCC has not yet come to fruition. The present review summarizes the aetiology of HPV-positive (HPV+) OPSCC and provides a detailed overview of HPV virology and molecular pathogenesis relevant to infection of oropharyngeal tissues. Methods of detection and differential gene expression analyses are also summarized. Future research into mechanisms that mediate tropism of HPV to oropharyngeal tissues, improved detection strategies and the pathophysiological significance of altered gene and microRNA expression profiles is warranted.

Fig. 1

Sites of incidence of (A) head and neck and (B) oropharyngeal squamous cell carcinoma.

Fig. 2. Distinct phenotypic features characteristic of (A) HPV+ OPSCC relative to (B) HPV− OPSCC

Nonkeratinizing hyperchromatic tumor cells with ill-defined borders, abundant mitoses, and areas of necrosis (A). Keratinizing tumor cells with abundant pink cytoplasm composed in discrete nests (B).

Fig. 3. HPV infection of oral mucosa

HPV (red) infects proliferating cells in the basal layer that are exposed by wounding. The virus replicates in synchrony with cellular DNA replication. The highest level of viral replication occurs in the granular layer, as expression of HPV E6 and E7 maintain proliferation of these normally terminally differentiated cells. Mature virions are released through the cornified layer.

Fig. 4. HPV genome organization

The viral genome of HPV is a double-stranded circular genome of approximately 8 kb transcribed as polycistronic mRNAs with 8 open reading frames. High-risk HPV genomes contain two viral promoters (*) encoding early (E) and late (L) genes.

Fig. 5. HPV E6 and E7 promote cellular transformation and development of malignant phenotype

Virions enter the cell via endocytosis (a) and are trafficked to the nucleus (b) where they persist in episomal form (c) or are integrated into the host genome (d). Both episomal and integrated viral DNA produce E6 and E7 (e). Interaction of E6 with p53 and the ubiquitin ligase E6-associated protein target p53 for proteasomal degradation (f) and prevents apoptosis. Retinoblastoma family tumor suppressor proteins including pRb, p130, and p107 interact with E7 (g) and are inactivated, resulting in release of E2F and promoting cell cucle progression. Together these functions of E6 and E7 promote cellular transformation (h). Adapted with permission from [13].

Fig. 6. Representation of HPV16 E6 structure and binding partners

HPV E6 proteins are approximately 150 amino acids and contain two zinc finger domains. Identified binding partners of the N- and C-terminal domains are indicated below. Adapted with permission from [118].

Fig. 7. Representation of HPV16 E7 structure and binding partners

HPV E7 proteins are approximately 100 amino acids and contain a single zinc finger domain. Three conserved regions designated CR1, CR2 and CR3 are homologous to Adenovirus E1A and SV40 large T antigen and are essential for viral oncogenesis. Identified binding partners of the N- and C-terminal domains are indicated below. Adapted with permission from [118].

Fig. 8. Common and distinct chromosomal profiles of HPV(+) vs HPV(−) HNSCC relative to HPV(+) cervical SCC (CxSCC)

Array-based comparative genomic hybridization identified specific chromosomal alterations in HPV(+) and HPV(−) SCC from head and neck or cervical tissue. Gain at 3q and losses at 11q were common in all sample groups while loss at 13q and gain at 20q were representative of HPV(+) disease, regardless of the tissue of origin. Adapted with permission from [134].