HPVIndependent Penile Carcinogenesis

Penile carcinomas that are not associated with hrHPV are thought to arise from the progression of precursor lesions at sites of chronic irritation or injury, such as lichen sclerosus. Although the causative agent of these lesions has not been completely elucidated, inflammation is recognized as a critical component of tumor development or progression in these cases.2

Studies evaluating the molecular biology of non-HPV associated penile cancer have suggested that, in general, gene alterations (i.e., p53 alterations, gene promoter methylation) are more frequent in non-HPV-associated penile carcinomas as compared to their HPV-mediated counterparts.26 Although these data should be interpreted with care as only small case series were compared, the phenomenon would be in line with studies on head and neck carcinomas.27 In head and neck carcinomas, HPV-associated cancers are characterized by the disruption of the pRb and p53 pathways by the viral oncoproteins and were found to be genetically different from those that did not contain HPV. The latter required alternative genetic damage to disrupt similar cellular pathways, including p53 gene mutations and methylation of tumor suppressor and tumor-related genes.

Indeed, several studies have identified nonviral mechanism(s) leading to the disturbance of the p14ARF/MDM2/p53 and/or p16INK4a/cyclin D/Rb pathways as critical components of HPV-independent penile carcinogenesis.4,28,29 Inactivation of p16INK4a by methylation of the CpG-rich gene promoter region has been described in 15-26%

of non-HPV associated penile cancers.15,26 Another plausible mechanism by which the p16INK4a /cyclin D/Rb pathway can be disrupted during penile carcinogenesis in the absence of hrHPV is overexpression of the polycomb group (PcG) gene BMI-1, which targets the CDKN2A locus (which encodes both p16INK4a and p14ARF). Overexpression of BMI-1 has been reported in 10% of hrHPV-negative cases.15 Mechanisms by which the p14ARF/MDM2/p53 pathway becomes inactivated in non-HPV-associated penile cancers include somatic mutations of the p53 gene. An inverse relation between the presence of mutations of the p53 gene or p53 stabilization, a feature of mutated, inactive p53, and HPV presence has been reported for penile carcinoma,26,30-32 although there is some contradictory evidence regarding the relation between p53 expression and HPV infection.29 Another mechanism by which the p14ARF/MDM2/p53 pathway can be disrupted during penile carcinogenesis in the absence of hrHPV is overexpression of the MDM2 gene product, a negative regulator of p53.33

Taken together, these studies show that the two carcinogenic routes, i.e., virus and nonvirus induced, can differ but do have similarities also. In other words, virus and nonvirus-induced modes may differ in their manner of disrupting cellular pathways by activity of the known viral oncogenes E6 and E7, or more direct, oncogene-activating /tumor suppressor gene (TSG)-inactivating mechanisms, respectively. Nonetheless, similar cellular targets are hit during the early genetic events in penile carcinogenesis in both pathways.

A few studies have been performed in which survival was correlated with the HPV status of the primary tumor with differing results. Some showed no survival difference between HPV-positive and -negative tumors,34,35 while others suggest a survival benefit for penile cancer patients with hrHPV-positive tumors over those with HPV-negative tumors.22,36 Though highly speculative, if the latter findings holds true, hrHPV-positive penile tumors may comprise a distinct molecular and clinical entity of which a survival benefit may be related to a lower degree of gross genetic alterations, as previously found in head and neck cancer,27 or increased immune surveillance due to the presence of viral epitopes.

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