Molecular Genetics of Penile Cancer


Penile cancer is a rare malignancy in the United States and Europe but has a much higher prevalence in certain geographical areas including South America and Africa. Compared with other urological malignancies, there remains a paucity of information regarding the molecular mechanisms involved in penile cancer carcinogenesis. It is generally understood that there are two separate molecular pathways that contribute to carcinogenesis, one of which is largely related to human papillomavirus (HPV) infection. The second mechanism is much less clearly understood and is related to a combination of factors including those influenced by environmental effects and somatic or epigenetic changes. However, there also remains an element of interplay between the two mechanisms that adds to the complexity of understanding the disease. The aim of this review is to outline the current understanding of the genetic factors, current research and future directions involved in understanding the disease.

Key Concepts

  • Penile cancer is a rare entity and the mechanisms behind its carcinogenesis are not completely understood.
  • It is generally understood that the pathogenesis of penile cancer may related to both HPV mediated and non-mediated mechanisms.
  • The ability of the human papillomavirus to lead to malignancy is dependent on breakdown of normal cell degradation mechanisms as well as cell cycle alterations leading to uninhibited cell proliferation.
  • Non‐HPV mediated pathogenesis has numerous potential mechanisms and remains an ongoing area of study.
  • Continued focus on centers of excellence as well as international collaborations will be needed to continue to develop a full understanding of the disease.

Keywords: penile cancer; malignancy; human papillomavirus; tumorigenesis; mutations; mTOR; inflammation

Figure 1. This illustration outlines the complex mechanisms involved in the current understanding of penile cancer tumorigenesis. Shown are both intercellular and extracellular mechanisms as well as those mediated by human papillomavirus (HPV) factors and those that are independent of this. Reproduced from C Protzel and P E Spiess (2013). Molecular Research in Penile Cancer—Lessons Learned from the Past and Bright Horizons of the Future? Int. J. Mol. Sci. 2013, 14(10), 19494–19505.


Andersson P, Kolaric A, Windahl T, et al. (2008) PIK3CA, HRAS and KRAS gene mutations in human penile cancer. Journal of Urology 179 (5): 2030–2034. DOI: 10.1016/j.juro.2007.12.040.

Baker TS, Newcomb WW, Olson NH, et al. (1991) Structures of bovine and human papillomaviruses. Analysis by cryoelectron microscopy and three‐dimensional image reconstruction. Biophysical Journal 60 (6): 1445–1456. DOI: 10.1016/S0006-3495(91)82181-6.

Bleeker MCG, Heideman DAM, Snijders PJF, et al. (2009) Penile cancer: epidemiology, pathogenesis and prevention. World Journal of Urology 27 (2): 141–150. DOI: 10.1007/s00345-008-0302-z.

Camus S, Menéndez S, Cheok CF, et al. (2007) Ubiquitin‐independent degradation of p53 mediated by high‐risk human papillomavirus protein E6. Oncogene 26 (28): 4059–4070. DOI: 10.1038/sj.onc.1210188.

Cardoso JC and Calonje E (2011) Cutaneous manifestations of human papillomaviruses: a review. Acta dermatovenerologica Alpina, Pannonica, et Adriatica 20 (3): 145–154. doi:00000232 [pii].

Chaux A, Munari E, Cubilla AL, et al. (2014) Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases. Histopathology 64 (6): 863–871. DOI: 10.1111/his.12338.

National Comprehensive Cancer Network Penile Cancer (Version 1. 2017). (Accessed April 11, 2017)

Di Lorenzo G, Buonerba C, Ferro M, et al. (2015) The epidermal growth factor receptors as biological targets in penile cancer. Expert Opinion on Biological Therapy 15 (4): 473–476. DOI: 10.1517/14712598.2015.993377.

De Paula AAP, Motta ED, Alencar RDC, et al. (2012) The impact of cyclooxygenase‐2 and vascular endothelial growth factor C immunoexpression on the prognosis of penile carcinoma. Journal of Urology 187 (1): 134–140. DOI: 10.1016/j.juro.2011.09.027.

De Villiers EM, Fauquet C, Broker TR, Bernard HU and Zur HH (2004) Classification of papillomaviruses. Virology 324 (1): 17–27. DOI: 10.1016/j.virol.2004.03.033.

Doorbar J (2006) Molecular biology of human papillomavirus infection and cervical cancer. Clinical Science 110 (5): 525–541. DOI: 10.1042/CS20050369.

Doorbar J (2015) Model systems of human papillomavirus‐associated disease. Journal of Pathology 238: 166–179. DOI: 10.1002/eft2.

Downes MR (2015) Review of in situ and invasive penile squamous cell carcinoma and associated non‐neoplastic dermatological conditions. Journal of Clinical Pathology 68 (5): 333–340. DOI: 10.1136/jclinpath-2015-202911.

Ferrandiz‐Pulido C, Masferrer E, Toll A, et al. (2013) MTOR signaling pathway in penile squamous cell carcinoma: pmTOR and peIF4E over expression correlate with aggressive tumor behavior. Journal of Urology 190 (6): 2288–2295. DOI: 10.1016/j.juro.2013.06.015.

Ferreux E, Lont AP, Horenblas S, et al. (2003) Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high‐risk human papillomavirus. Journal of Pathology 201 (1): 109–118. DOI: 10.1002/path.1394.

Funk JO, Waga S, Harry JB, et al. (1997) Inhibition of CDK activity and PCNA‐dependent DNA replication by p21 is blocked by interaction with the HPV‐16 E7 oncoprotein. Genes & Development 11 (16): 2090–2100. DOI: 10.1101/gad.11.16.2090.

Ghittoni R (2015) The role of human papillomaviruses in carcinogenesis. Ecancermedicalscience 9 (4): 307–313. DOI: 10.3332/ecancer.2015.526.

Golijanin D, Tan JY, Kazior A, et al. (2004) Cyclooxygenase‐2 and microsomal prostaglandin E synthase‐1 are overexpressed in squamous cell carcinoma of the penis. Clinical Cancer Research 10 (3): 1024–1031.

Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M (1999) The oncogene and Polycomb‐group gene bmi‐1 regulates cell proliferation and senescence through the ink4a locus. Nature 397 (6715): 164–168. DOI: 10.1038/16476.

Kang S, Bader AG and Vogt PK (2005) Phosphatidylinositol 3‐kinase mutations identified in human cancer are oncogenic. Proceedings of the National Academy of Sciences of the United States of America 102 (3): 802–807. DOI: 10.1073/pnas.0408864102.

Kayes O, Ahmed HU, Arya M and Minhas S (2007) Molecular and genetic pathways in penile cancer. Lancet Oncology 8 (5): 420–429. DOI: 10.1016/S1470-2045(07)70137-7.

Liggett WH and Sidransky D (1998) Role of the p16 tumor suppressor gene in cancer. Journal of Clinical Oncology 16 (3): 1197–1206.

Mannweiler S, Sygulla S, Winter E and Regauer S (2013) Two major pathways of penile carcinogenesis: HPV‐induced penile cancers overexpress p16ink4a, HPV‐negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression. Journal of the American Academy of Dermatology 69 (1): 73–81. DOI: 10.1016/j.jaad.2012.12.973.

Nguyen ML, Nguyen MM, Lee D, Griep AE and Lambert PF (2003) The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo. Journal of Virology 77 (12): 6957–6964. DOI: 10.1128/JVI.77.12.6957.

Poetsch M, Schuart B, Schwesinger G, Kleist B and Protzel C (2007) Screening of microsatellite markers in penile cancer reveals differences between metastatic and nonmetastatic carcinomas. Modern Pathology 20 (10): 1069–1077. DOI: 10.1038/modpathol.3800931.

Poetsch M, Hemmerich M, Kakies C, et al. (2011) Alterations in the tumor suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas. Virchows Archiv 458 (2): 221–229. DOI: 10.1007/s00428-010-1007-4.

Pópulo H, Lopes JM and Soares P (2012) The mTOR signalling pathway in human cancer. International Journal of Molecular Sciences 13 (2): 1886–1918. DOI: 10.3390/ijms13021886.

Stankiewicz E, Prowse DM, Ng M, et al. (2011) Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas. PLoS One 6 (3): e17517. DOI: 10.1371/journal.pone.0017517.

You J, Croyle JL, Nishimura A, Ozato K and Howley PM (2004) Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 117 (3): 349–360. DOI: 10.1016/S0092-8674(04)00402-7.

Zargar‐Shoshtari K, Spiess PE, Berglund AE, et al. (2015) Clinical significance of p53 and p16ink4a status in a contemporary North American Penile Carcinoma Cohort. Clinical Genitourinary Cancer 14: 346–351.

Zhang P, Nouri M, Brandsma JL, Iftner T and Steinberg BM (1999) Induction of E6/E7 expression in cottontail rabbit papillomavirus latency following UV activation. Virology 263 (2): 388–394. DOI: 10.1006/viro.1999.9950.

Further Reading

Kuasne H, Marchi FA, Rogatto SR and de Syllos Colus IM (2013) Epigenetic Mechanisms in Penile Carcinoma. International Journal of Molecular Sciences 14 (6): 10791–10808. DOI: 10.3390/ijms140610791.

Rodney S, Feber A, Arya M and Muneer A (2015) Molecular markers in penile cancer. Current Problems in Cancer 39 (3): 137–145. DOI: 10.1016/j.currproblcancer.2015.03.005.

Tolstov Y, Hadaschik B, Pahernik S, Hohenfellner M and Duensing S (2014) Human papillomaviruses in urological malignancies: a critical assessment. Urologic Oncology 32 (1:46.): e19–e27. DOI: 10.1016/j.urolonc.2013.06.012.

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McCormick, Barrett, Baumgarten, Adam, and Spiess, Philippe E(May 2017) Molecular Genetics of Penile Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024928]