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Title: The role of DNA replication licensing proteins in urological cancer management
Author: Dudderidge, Tim
ISNI:       0000 0004 5358 2243
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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The non-invasive diagnosis of cancer and assessment of disease severity are both important challenges facing urologists managing patients with kidney, bladder and prostate cancer. Both challenges can potentially be met through the use of molecular markers of cancer that are present in blood, urine and biopsy material from tumours. In this thesis I explore the use of DNA replication licensing proteins, key components of the DNA replication machinery, as diagnostic, prognostic and predictive factors for urological cancers. The main markers studied, Mcm2, McmS and geminin are crucially important as their expression is closely linked with cell cycle activation and control in normal and malignant cells. Loss of growth control rapidly leads to abnormal expression of these proteins. Furthermore, by combined analysis with the well-known cell cycle marker Ki67, we have learned more about the cell cycle kinetics in urological tumours. The studies in this thesis include the examination of DNA replication licensing protein expression in kidney and prostate cancer tissue. In the study of kidney cancer, my coworkers and I examined a series of tumours from patients who had undergone nephrectomy for renal cell carcinoma. We showed that increased Mcm2 expression is associated with reduced disease-free survival time and that Ki67 is an independent predictor of disease free survival in this disease. In prostate cancer we investigated linkages between the MEKS/ERKS pathway and DNA replication licensing during prostate carcinogenesis. We confirmed that dysregulation of upstream pathways leads 8 to increased expression of DNA replication licensing proteins. Importantly, we showed that Mcm2 was an independent prognostic marker in prostate cancer. The latter two studies examine the use of Mcm5 as a urinary diagnostic marker for prostate and bladder cancer. We were able to demonstrate that in a series of men at a variety of stages of prostate cancer, elevated urinary Mcm5 levels were present in a very large proportion of men with prostate cancer and mostly absent in patients with a benign diagnosis (82% sensitivity, 73-93% specificity). In a much larger study, the largest to date to evaluate a commercialized comparative marker NMP22, we determined that the academic Mcm5 assay was a highly accurate diagnostic marker for bladder cancer. Interestingly, we found that the combination of Mcm5 with NMP22 improved the detection of bladder cancer and allowed the identification of95% of patients with clinically significant disease. In the discussion section ofthis thesis I conclude that the DNA replication licensing proteins offer researchers a number opportunities to develop diagnostic and predictive markers for urological cancer. Clinical trials of a commercialized Mcm5 assay (UrosensTM) are underway and may lead to novel minimally invasive approaches to urological cancer detection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available