HPVMediated Penile Carcinogenesis

HPV is associated with anogenital tumor formation and is an important factor in the development of in-situ and invasive epithelial tumors. Our understanding of HPV DNA integration into the human genome has resulted from research investigating SCC of the cervix and from the development of an HPV-specific quadrivalent vaccine. HrHPV-associated penile cancers are thought to arise from the progression of precursor lesions caused by an hrHPV infection. HrHPV infections have a strong association with anogenital tumor formation, particularly cervical cancer.

HPV is a family of epitheliotropic, small double-stranded DNA viruses of approximately 8,000 bp. Sexual transmission is the most common route for viral infection, although oral and vertical transmission are also possible.10 Epidemiologic research has classified 15 genotypes of HPV as high-risk, based on their association with cervical cancer, i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82, and three types as probably high-risk, i.e., HPV 26, 53, and 66.11 Recent literature reviews of data available for Europe, North America, South America, and Asia, reported an overall HPV prevalence in penile carcinomas of approximately 47%.3,8 The contribution of the different HPV types among HPV-positive penile cancers varies as follows: HPV-16 (60.23%), HPV-18 (13.35%), HPV-6/11 (8.13%), HPV-31 (1.16%), HPV-45 (1.16%), HPV-33 (0.97%), HPV-52 (0.58%), other types (2.47%).3

The viral genome contains early (E) regions encoding proteins for replication, regulation, and modification of the host cytoplasm and nucleus, and late (L) regions that encode capsid proteins. Studies on the viral proteins E6 and E7 revealed their binding to and inactivation of the cellular p53 and Rb tumor suppressor gene products, respectively,1213 thereby controlling cellular proliferation and apoptosis. The E6 and E7 gene products of the oncogenic HPV types have an initiating role in the transformation process, but are also relevant for the maintenance of the transformed phenotype of the infected cells, as interference with their expression may trigger senescence and apoptosis.

Knowledge from cervical cancer development, a tumor for which hrHPV infection is a necessary cause, indicates that a persistent infection with hrHPV is the initiating causative event. There is no indication that this would be different for hrHPV-associ-ated penile cancers. In fact, functional evidence for an initiating role of hrHPV in the transformation process comes partly from studies that used penile foreskin keratino-cytes as a model system.14 Although essential, the hrHPV infection is not sufficient to induce frank cancer. Subsequent genetic and epigenetic alterations in the host cell are necessary for an hrHPV-infected cell to become fully malignant. As such, hrHPV-associated penile carcinogenesis is considered to be mechanistically equivalent to hrHPV-mediated cervical carcinogenesis.14

Following infection of the mucosal epithelium by hrHPV, it is assumed that generally productive viral infections arise in which the viral life cycle and virion production are strongly coupled to the differentiation program of the infected epithelium. Only when this tight regulation becomes lost, by a mechanism not yet fully understood, uncontrolled expression of the viral oncogenes E6 and E7 may occur in proliferating basal and parabasal epithelial cells, a phenomenon that distinguishes the process of cell transformation from a productive viral infection. By disturbance of the p14ARF/MDM2/p53 and p16INK4a/cyclin D/Rb pathways in the (para)basal cells, oncogenic HPV types interfere with control of the cell division cycle and apoptosis. A strong immunostaining for p16INK4A in HPV-associated penile cancers, consistent with an active role for HPV in interfering with the retinoblastoma pathway (i.e., functional inactivation of pRb by hrHPV E7 protein, which results in free E2F and the reciprocal overexpression of p16INK4a), has been described.1516 The disturbance of cell division and apoptosis triggers a state of chromosomal instability and further drives the carcinogenic process. The subsequent host-cell genetic and epigenetic events involved in hrHPV-induced penile carcinogenesis are not extensively studied to date, but are likely to be similar to those involved in other hrHPV-associated anogenital cancers, e.g., telomerase activation, and gene promoter hypermethyla-tion (see below).

Based on similar prevalences of HPV (mainly HPV-16) and their precursor lesions,2 etiological similarities have been suggested between tumors from the vulva and the penis. Yet, differences should be taken into account. Vulvar cancer tends to have a bimodal age distribution. HPV-associated cancers manifest at an earlier age than HPV-unrelated cancers (i.e., seventh or eighth decade of life).1718 For penile cancer these data are contradictory. Cubilla et al.19-21 reported an age difference between HPV-positive and negative cases, while another study found similar peak incidence for both HPV-mediated and non-HPV-associated penile cancers (i.e., average 64 years).22

From a molecular point of view, HPV-dependent carcinogenesis of the penis has been suggested to resemble that of the cervix.2,23 Despite a likely common ground based on the shared causative agent, differences between hrHPV-associated penile and cervical carcinoma should also be considered. First, the worldwide incidence of HPV-associated penile carcinoma is very rare as compared to cervical cancer, whereas penile and cervical hrHPV infections are equally common.24,25 Second, the peak incidence of penile cancer is approximately 20-30 years later than that of cervical cancer.22 These observations suggest tissue and/or hormone-specific variables influencing the clinical course of an hrHPV-infection and the potential accompanied oncogenic process. The penile epithelium likely comprises a less favorable environment for virus-induced transformation than the cervical transformation zone, in which cervical cancer arises.

Thus, despite penile carcinogenesis sharing some specific genetic and epigenetic alterations which are known to be involved in hrHPV-mediated carcinogenesis at different anatomical sites including those related to cervical and vulvar cancer, these should be interpreted with caution in relation to penile carcinogenesis. Further research is warranted to reveal the precise role of these molecular events in HPV-associated penile carcinogenesis.

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