The Oncogenic Potential of Human Papillomaviruses: A Review on the Role of Host Genetics and Environmental Cofactors

V.K. Madkan; R.H. Cook-Norris; M.C. Steadman; A. Arora; N. Mendoza; S.K. Tyring

Disclosures

The British Journal of Dermatology. 2007;157(2):228-241. 

In This Article

Summary and Introduction

Human papillomaviruses (HPVs), with over 100 genotypes, are a very complex group of human pathogenic viruses. In most cases, HPV infection results in benign epithelial proliferations (verrucae). However, oncogenic types of HPV may induce malignant transformation in the presence of cofactors. For example, over 99% of all cervical cancers and a majority of vulval, vaginal, anal and penile cancers are the result of oncogenic HPV types. Such HPV types have been increasingly linked to other epithelial cancers involving the skin, larynx and oesophagus. Although viral infection is necessary for neoplastic transformation, evidence suggests that host and environmental cofactors are also required. Research investigating HPV oncogenesis is complex and quite extensive. The inability to produce mature HPV virions in animal models has been a major limitation in fully elucidating the oncogenic potential and role of associated cofactors in promoting malignant transformation in HPV-infected cells. We have reviewed the literature and provide a brief account of the current understanding of HPV oncogenesis, emphasizing the role of genetic susceptibility, immune response, and environmental and infectious cofactors.

Human papillomaviruses (HPVs) are a large group of small, nonenveloped, double-stranded DNA viruses. Infection with HPV typically leads to benign epithelial proliferations; however, a growing number of viral subsets has been associated with epithelial cancers. However, most cases do not progress to cancer, even in patients infected with these oncogenic, 'high-risk' subsets. Malignant transformation, if it occurs, tends to occur only after a long latency period, reflecting that infection with HPV is necessary but not sufficient for the development of HPV-associated cancers.[1]

The first link between HPV infection and epithelial cancer came from patients with epidermodysplasia verruciformis (EV).[2,3] Individuals with EV develop multiple atypical verrucous lesions which may progress into squamous cell carcinoma (SCC) especially in sun-exposed areas.[3] Genotyping has allowed the isolation of a group of HPV types known as EV-associated HPV types. In addition, advances in molecular technology have allowed a number of additional oncogenic HPV types to be detected in many types of epithelial cancer.

HPV types may be classified in many ways, including the locations on the body each virus tends to infect and its potential for oncogenesis, i.e. 'high-risk' vs. 'low-risk' types. In this section, we will briefly review the most common HPV types and attempt to classify them according to these criteria. HPVs induce neoplastic transformation in cells of the skin and mucosal epithelium. These neoplastic transformations vary widely in severity from benign warts to highly malignant cancers, depending largely on the type of HPV present. For example, benign verrucae are known to be associated with HPV types 1-4, 7, 10, 27, 40, 41, 43, 57, 63 and 65.[4] In contrast, HPV types 3, 5, 8, 10, 17 and 20 have been isolated from lesions in patients with EV.[5] Additionally, HPV types 5 and 8 have been associated with neoplasms in immunocompromised hosts.[4] It is not currently known why HPV types 3 and 10 may be associated with both benign verrucae and EV lesions, but perhaps a cofactor is necessary for malignant transformation. HPV types 6 and 11, which tend to reside in cells of the anogenital region, are known to cause recurrent juvenile laryngeal papillomas in infants of infected mothers as well as anogenital condyloma acuminatum, a benign but cosmetically unfavourable sexually transmitted disease in adults. Multiple HPV types have been implicated in the promotion of cervical SCC development. The HPV types found in cervical neoplastic cells were classified by Muñoz et al. into those associated with low (6, 11, 13, 40, 42-44, 54, 61, 62, 70, 72, 74, 81) and high (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82) risk of progression to malignancy. In addition, the authors concluded that HPV types 26, 53 and 66 should be considered probably carcinogenic due to the extremely small number of affected patients.[6]

For many years, the significance of finding HPV DNA in cancerous lesions was debated. This was in part due to a lack of an animal model to study HPV oncogenesis. Eventually, the ability to clone viral genomes and advances in molecular protein studies allowed the molecular mechanisms involved in HPV oncogenesis to be investigated. This led to the concept of 'low-risk' and 'high-risk' HPV types based on isolation from benign and malignant lesions, respectively. On the molecular level, malignant cells from cervical carcinoma (CC) cell lines have been shown to selectively retain and express viral genes E6 and E7.[3] The E6 gene product binds to the p53 tumour suppressor gene and induces its degradation. The E7 gene codes for a product that targets and binds to the tumour suppressor retinoblastoma gene product (pRb), phosphorylating and therefore inactivating this protein. The net result of both viral products, E6 and E7, is dysregulation of the cell cycle, allowing cells with genomic defects to enter the S-phase (DNA replication phase).[7] Further studies have documented additional evidence of the oncogenic potential of E6/E7, including the constant expression of E6/E7 and absence of corresponding regulatory mechanisms in tumour cell lines.[8] These oncoproteins have also been shown to promote chromosomal instability as well as to induce cell growth and immortalize cells. Moreover, blocking E6/E7 gene function causes some malignant cells to revert to a benign phenotype. Variable expression of the E6/E7 gene products has been found among HPV low-risk and high-risk types, with less expression in the former.[3] In addition, low-risk HPV oncoproteins were also thought to not function as efficiently. This was supported by studies indicating an absence of p53 inactivation and degradation by low-risk HPV E6 protein.[9]

The lack of cancer development in every patient infected with high-risk HPV coupled with a long latency period prior to malignant transformation suggests that other events are required for full transformation. Interestingly, in benign lesions (e.g. warts), the HPV genome is present as an episome (circular and nonintegrated), whereas in malignant lesions (invasive CC lines) the genome is typically integrated.[10] Integration of viral DNA has been suggested to alter viral gene expression. The integration site in the viral genome typically encompasses the E2 gene region, which codes for an E6/E7 gene-regulatory protein. Therefore, viral genome integration has the potential to dysregulate the E2 gene thus leading to a lack of E6 and E7 gene repression.[11,12] As stated by Wang and Hildesheim,[10] genome integration may initiate an irreversible cascade of events leading to impaired function of tumour suppressor genes, genomic instability and cell immortalization.

The E2 gene product has also been shown to cause cell cycle dysregulation independently of E6/E7 activity. For example, in high-risk HPV types only, the E2 protein has been shown to promote a mitotic block, often followed by metaphase-specific apoptosis. In addition, polyploidy, chromosomal mis-segregation and centrosome amplification may be caused by the E2 proteins specific to high-risk HPV types. The end result of each of these aberrations is genomic instability leading to increased risk of oncogenesis. These findings raise the possibility that high-risk HPV-specific E2 proteins are themselves a significant oncogenic component of high-risk papillomaviruses, in addition to their role in gene regulation.[13]

HPVs are extremely species specific, making animal models insufficient for studying HPV oncogenesis in humans. Cervical precancerous lesions have been well studied, and serve as a model for mucocutaneous HPV oncogenesis. Due to the prolonged transformation period typical of these cervical lesions, the role and importance of viral and host cofactors have been well established. Immunosuppressed individuals and those with EV have been important models in understanding cutaneous HPV oncogenesis. Frequent isolation of EV-specific or EV-related HPVs within cutaneous tumours in the general population, as well as in immunosuppressed individuals, makes EV an excellent model of HPV-associated carcinogenesis.

In this review, the role of host genetics and immune response as well as environmental cofactors associated with the development of HPV-induced neoplasms will be discussed. Discussion of host genetic factors will include associated polymorphisms and susceptibility loci; discussion of host immune response will include the significance of host immune-compromising conditions, as evidenced by organ transplant recipients and human immunodeficiency virus (HIV)-positive individuals; discussion of associated environmental cofactors will include those with significant supportive evidence including tobacco, ultraviolet (UV) and ionizing radiation, diet, and obesity; discussion of coinfection with other viral and bacterial pathogens will include herpes simplex virus 2 (HSV-2) and Chlamydia trachomatis.

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