Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Abstract

Many human papillomavirus (HPV)-positive high-grade lesions and cancers of the uterine cervix harbor integrated HPV genomes expressing the E6 and E7 oncogenes from chimeric virus-cell mRNAs, but less is known about HPV integration in head and neck cancer (HNC).Mucosal high-risk (HR) human papillomavirus (HPV) types are found in nearly 100% of carcinomas of the uterine cervix, many anogenital cancers, and ϳ25% of head and neck cancers (HNC) (9, 13, 42). The most common HR HPV is type 16, found in over 50% of cervical cancers and 90 to 95% of HPVpositive HNCs. In persistent infection, HPV genomes are maintained as circular, unintegrated plasmids that persist in the nuclei of infected cells (see Fig. 1A). In contrast, HR HPV DNA found in cervical cancer specimens is frequently disrupted and integrated in the cellular genome in a way that potentially alters the expression program of the viral early gene region and/or the host genome (2,5,8,21,23,24,31,43). The integrated HR HPV fragments in high-grade precancerous cervical lesions, cervical carcinomas, and derived cell lines express the viral transforming genes E6 and E7 from chimeric virus-cell mRNAs, while the downstream early genes that are required for viral replication and regulated viral gene expression are disrupted or silenced (33,37,47,55). Further, chimeric virus-cell mRNAs may be more stable than the viral early mRNAs, which harbor a 3Ј destabilization motif (20,53). In addition, some integration sites in cervical cancer and precursor lesions have been found near potential growth control genes (11,40,55).Advances in keratinocyte culture techniques have permitted the study of the life cycle of HR HPV types that replicate efficiently and persist in primary human keratinocytes, such as 34,35), and to a more limited extent 36). However, relatively little is known about the progression of the infected cell toward a malignant phenotype in vivo or in culture. While some cervical cancers have been shown to harbor extrachromosomal HPV DNA, it is apparent that integration of viral DNA accompanied by disruption of the integrity of the HR HPV genomes represents a common, albeit not absolutely obligatory, step associated with carcinogenic progression associated with the genital tract (42, 57). The majority of cervical carcinomas caused by the two most common HR HPV types, HPV-16 and -18, contain integrated viral sequences (52) that express E6-E7 from chimeric, spliced virus-cell transcripts. However, the genetic structure and expres-

Human Papillomavirus-Related Head and Neck Cancer

“…In an in-vitro study of HPV-transfected keratinocytes, integration sites were detected in various chromosomal locations but also in or near genes encoding growth control proteins [32]. This supports the idea of clonal selection by HPV integration towards more aggressive tumors.…”

Prevalence of Human Papillomavirus Infection in Oral Squamous Cell Carcinoma: a Case-control Study in Wuhan, China

“…More than 200 different human papillomavirus (HPVs) types have been characterized (Psyrri et al, 2008), and at least 40 types can infect human genital tract (Munoz et al, 2003), of which HPV16 and HPV18 as main high-risk types are more closely linked with malignant tumors. Recent study has shown that HPV genomes integrated in head and neck cancer express chimeric virus-cell mRNAs, which is similar to those found in cervical cancers (Lace et al, 2011). HPVassociated OSCCs tend to be poorly differentiated with basaloid features in histology, frequently presenting at an advanced stage.…”

Mate pair sequencing of oropharyngeal squamous cell carcinomas reveals that HPV integration occurs much less frequently than in cervical cancer

“…In OPSCC, data concerning the frequency of HPV integration are limited [15][16][17]. We previously reported that we could detect no evidence of HPV integration from 40 HPV 16 positive OPSCC by using restriction site oligonucleotide PCR (RSO-PCR) [18], while the same method was able to identify HPV cellular junctions in many cervical cancers [5,11,19,20].…”