Introduction Molecular Concept of Penile Carcinogenesis

Penile cancer is a rare disease, particularly in developed countries.1 Large case series for molecular studies are relatively limited. Only a few, albeit important, studies evaluating the molecular etiopathogenesis of penile carcinoma have been published to date. Based on these studies, a model of penile carcinogenesis describing the molecular alterations that accumulate during the pathogenesis of penile carcinoma has been proposed.2 In this molecular concept, the etiology of penile carcinoma is recognized to be heterogeneous in nature with evidence pointing to at least two independent carcinogenic routes, i.e., virus and nonvirus induced.

About half of penile cancers are caused by an infection with high-risk (often also referred to as "oncogenic") human papillomavirus (hrHPV), mainly type HPV-16. 3-8 The remaining penile cancers arise independent of hrHPV infection. A similar division has also been described for vulvar and head and neck carcinomas.9 Although the molecular routes of disruption differ in multiple ways - particularly related to the early genetic events and the activity of the known viral oncogenes E6 and E7 -common cellular pathways are disrupted at initial and later stages during penile carcinogenesis in both virus and nonvirus-induced modes. Penile cancers are likely to be initiated by interference with the cellular p14ARF/MDM2/p53 and/or p16INK4a/ cyclin D/Rb pathways, either by viral (i.e., HPV) or nonviral (i.e., mutation, gene promoter hypermethylation, etc.) mechanisms. This may lead to uncontrolled cell division and reduced apoptosis, and may trigger a state of chromosomal instability that further drives the carcinogenic process. More common molecular events in late(r) stage penile carcinogenesis include altered expression of genes involved in disease progression, invasion, angiogenesis, and metastasis.

D.A.M. Heideman (*) Department of Molecular Pathology,

VU University Medical Center, Amsterdam, 1081 HV, The Netherlands

A. Muneer et al. (eds.), Textbook of Penile Cancer, 13

DOI 10.1007/978-1-84882-879-7_2, © Springer-Verlag London Limited 2012

Carcinogenic route

Early molecular events

leading to disruption of

and resulting in

Late(r) molecular events

resulting in

HPV-induced

p16 / CyclinD/ CDK/Rb

uncontrolled cell division and reduced apoptosis

immortalisation angiogenesis invasion metastasis

Viral oncogenes hrHPV E6 and hrHPV E7

Altered expression of genes involved in disease progression, invasion, angiogenesis and metastasis a.o. ras myc telomerase E-cadherin MMPs

PGE2 synthase COX

(epi) genome

Non-virus induced

Oncogene-activating and/or TSG-inactivating mechanisms, like

- gene promoter methylation

- gene mutation

- gene overexpression

p14 / MDM2 / p53

Fig. 2.1 Molecular concept of penile carcinogenesis. Schematic overview of molecular events during early and late(r) stages of penile carcinogenesis according to mode of pathogenesis, i.e., virus or nonvirus induced

Fig. 2.1 Molecular concept of penile carcinogenesis. Schematic overview of molecular events during early and late(r) stages of penile carcinogenesis according to mode of pathogenesis, i.e., virus or nonvirus induced

An overview of the molecular pathogenesis of penile cancer is presented in Fig. 2.1, and will be further discussed in this chapter.

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