Kayes, OJ; (2015) Aberrant regulation of the DNA replication licensing system and genomic instability in penile squamous cell carcinoma. Doctoral thesis , UCL (University College London).

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Abstract

Penile cancer is a rare urogenital malignancy associated with an unusual geographical variability. Unifying hypotheses to explain this diversity include variations in human papilloma virus (HPV) infection and distinct socioeconomic influences. However, our understanding of the molecular drivers for penile carcinogenesis remains deficient. Furthermore, current prognostic and predictive tools for the clinical management of men with penile cancer have limited discriminatory roles. Radical surgery remains the cornerstone of treatment and effective adjuvant treatments are lacking. Despite improvements in surgical techniques and diagnostic methods, clinical outcomes appear to have plateaued in recent times. The DNA replication licensing factors are important cell cycle regulatory proteins which are showing promise as novel biomarkers and therapeutic targets in a broad range of tumour types. It may be possible to exploit the unique properties of the replication licensing system; as a relay station for upstream, signalling pathways, in order to develop utilitarian biomarkers and therapeutic targets for managing men with PeScc. In this thesis, I show that there is aberrant regulation of the DNA replication licensing system in PeScc. Importantly, I demonstrate that the dysregulation of these molecules is associated with aggressive, genomically unstable tumour phenotypes, which in turn translates into important prognostic information with regards to patient survival. Furthermore, I have shown that multiparameter expression analysis of these proteins allows assessment of cell cycle kinetics in individual pathological specimens, parameters linked to the biological behaviour of these tumours. This novel form of cell cycle biomarker analysis may also be of value as a predictive test for assessing the therapeutic effect of cell cycle phase specific anti-cancer agents or mechanistic drugs targeting the cell cycle machinery. Collectively, these studies highlight the prognostic, predictive and therapeutic utility of the DNA replication licensing system in PeScc.

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