Rodney, Simon Nicholas;
(2021)
Molecular heterogeneity of invasive penile cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Penile cancer is a rare and mutilating disease. Due to the paucity of basic, molecular and translational work, new treatment options have not been forthcoming and the disease has arguably been neglected, and patients have poor outcomes. This thesis explores the molecular biology of advanced squamous cell penile carcinoma by assessing its genetic and epigenetic aberrations, and transcriptomic changes. For each patient, five tumour regions were profiled in detail and compared with a matched control sample. When compared with other cancers, penile cancer appears to have a high tumour mutational load with high intra-tumour heterogeneity. Evidence for the clonal integration of HPV into the human genome was found. HPV positive samples are associated with APOBEC mutational changes and increased expression of DNMT1 and DNMT3A methyltransferases. TP53 was found to be an early clonal driver in the HPV negative samples, whereas mutations in mTOR or PIK3CA were found to be early clonal drivers in HPV positive samples. Potentially targetable mutations, such as EGFR, were only ever found to be subclonal in this small cohort. Other targetable mutations that were found to be early and shared throughout the primary tumour included DDR2 and cMET. Increased expression of immune checkpoint inhibitory proteins such as CTLA4 were found throughout all samples, providing preliminary evidence that checkpoint blockade could be effective in penile cancer. These findings suggest that penile cancer is a heterogeneous disease with remarkably different genetic and epigenetic profiles for HPV positive and HPV negative disease. These tumours display large amounts of intra-tumour heterogeneity and so may prove difficult to successfully treat with more traditional targeted therapies against tyrosine kinases. However, there is evidence that immune checkpoint blockade may prove to be efficacious in these patients and further work should be undertaken to examine this in more depth.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Molecular heterogeneity of invasive penile cancer |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10126455 |
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