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Molecular Genetic Predictors of Prostate Cancer Progression After Molecular genetic predictors of prostate cancer progression after radical prostatectomy Simon RJ Bott MB.BS, FRCS (Eng). The Prostate Cancer Research Centre, University College London. Dissertation for the degree of Doctor of Medicine University of London, 2005. UMI Number: U592749 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592749 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Acknowledgements I would like to thank the following people for providing support, inspiration and guidance in the generation o f this thesis. Professor Roger Kirby, Professor of Urology, St George’s Hospital, London. Dr M Constance Parkinson, Consultant Histopathologist, UCL Hospitals Trust, London. Dr Joel Hooper, Senior Scientist, The Genome Centre, William Harvey Research Institute, Queen Mary's School of Medicine, London. Dr Charles Mein, Laboratory Manager, The Genome Centre, William Harvey Research Institute, Queen Mary's School of Medicine, London. Dr Chris Jones, Senior Lecturer, Chester Beatty Research Laboratories, London. Dr Garreth Griffiths, Senior Medical Statistician, MRC Clinical Trials Unit, London. Dr David Hudson, Lead Scientist, Prostate Stem Cell Laboratory, Institute of Cancer Research, Surrey. Dr Magali Williamson, Senior Lecturer, Prostate Cancer Research Centre, London. Professor John Masters, Professor of Cellular Pathology, Prostate Cancer Research Centre, London. And thanks also for their financial support for this project. British Urological Foundation and AstraZeneca. The Prostate Research Campaign UK. Everard Goodman. 2 To Emma, Freddie and Oscar 3 Contents Abstract Chapter 1 Introduction 1.1 Introduction 1.2 Incidence of prostate cancer 1.3 Prostate anatomy and physiology 1.4 Natural history of prostate cancer and active surveillance 1.5 Staging prostate cancer 1.6 Grading prostate cancer a) Gleason grade b) Tumour multifocality 1.7 Localised prostate cancer a) Presentation b) Patient selection for radical prostatectomy c) Preoperative predictors of outcome 1. Clinical stage 2. PSA 3. Biopsy Gleason score 4. Biopsy features 5. Preoperative imaging 6. Circulating prostate cells 7. PSA density, PSA ffeeitotal ratio, PSMA 1.8 Post-operative predictors of outcome a) Radical prostatectomy Gleason score b) Pathological stage c) Positive surgical margins d) Tumour volume e) Lymphovascular invasion f) DNA ploidy 1.9 Neoadjuvant androgen deprivation 1.10 Management of recurrent disease after radical prostatectomy a) Definition and timing of relapse b) Site of relapse c) Treatment of relapse 4 1.11 Molecular changes in prostate cancer a) Background 1. Oncogenes 2. Tumour suppressor genes b) Hereditary prostate cancer 1. Candidate genes 2. Low penetrance polymorphisms c) Somatic changes 1. Early prostate cancer 2. Metastatic prostate cancer 3. Hormone refractory prostate cancer 4. Telomerase 1.12 Molecular markers in cancer a) DNA markers and Microarray technology b) Allelic imbalance c) Microsatellite instability d) Hypermethylation e) Mitochondrial DNA mutation f) Viral DNA g) RNA markers h) Protein markers 1.11 Summary Chapter 2 Patient selection Aim 2.1 Introduction 2.2 Methods a) The UCL Radical Prostatectomy Database b) Consent c) Identifying two groups of patient 1. Tumour stage 2. Exclsuion criteria 3. Biochemical outcome 4. Matching 2.3 Results a) The Radical Prostatectomy Database b) Patient matching c) Comparison between the groups d) The unmatched patients 2.4 Discussion 2.5 Summary 5 Chapter 3 Materials and Methods Aim 3.1 The pathological specimen and tumour dissection 3.2 DNA extraction 3.3 DNA amplification a) Principles of the polymerase chain reaction b) Microsatellite marker selection c) PCR optimisation 1. DNA concentration 2. Marker concentration 3. Magnesium chloride concentration 3.4 Genotyping 3.5 Analysing the data Chapter 4 Results 4.1 Allelic imbalance 4.2 Results a) Interpreting electropherograms b) Allelic imbalance and PSA outcome 4.3 Discussion 4.4 Study limitations Chapter 5 The p21WAF1/CIP1 gene is inactivated in metastatic prostatic cancer cell lines by promoter methylation Aim 5.1 Introduction 5.2 Materials and Methods a) Cell culture and treatment b) Cell counting c) p 2i WAFI/CIPI gene expression 1. RNA extraction 2. cDNA 3. Primer design 4. Reverse Transcriptase-Polymerase Chain Reaction 5. Agarose gel electrophoresis 6 d) Promoter sequencing 1. DNA extraction 2. Sodium bisulphite modification 3. PCR 4. DNA extraction from agarose gel 5. Sequencing reaction 5.3 Results a) Cell culture b) RT-PCR c) Sequencing the p21HAF 1CIPI promoter 5.4 Discussion 5.5 Conclusions Chapter 6 Conclusions and future directions Appendix Appendix 1. Power calculation: based on McNemar’s test Appendix 2. Preoperative features of matched patients Appendix 3. Radical prostatectomy pathological findings in matched patients Appendix 4. PSA follow-up in matched patients Appendix 5. Procedure for staining with haematoxylin and eosin Appendix 6. The ABgene™ DNA block 96well plates arranged for genotyping Appendix 7. Features of the polymorphic markers used in the allelic imbalance study References Abbreviations 7 Tables and Figures Table 1.1. Outcome of patients undergoing active surveillance. Table 1.2. TNM classification of prostate cancer. Table 1.3. Comparison of body coil and endorectal coil magnetic resonance imaging at detecting extracapsular extension of prostatic cancer. Table 1.4. Risk factors for recurrence after radical prostatectomy. Table 1.5. Actuarial biochemical free survival and prostate tumour stage. Table 1.6. The site of non-iatrogenic (extraprostatic) solitary positive surgical margins after radical prostatectomy. Table 1.7. Biochemical recurrence and positive surgical margins. Table 1.8. Comparison of Gleason score, pathological stage and timing of PSA recurrence by site of recurrence after anatomic radical prostatectomy. Table 1.9. Chromosomal loci reported to contain hereditary prostate cancer genes. Table 2.1. Preoperative and pathological features of the UCL Radical Prostatectomy database. Table 2.2. The number and site of positive surgical margins from The UCL Radical Prostatectomy database. Table 2.3. Patient matching. Table 2.4. The site of solitary positive surgical margins. Table 2.5. Patients with 0, 1 or >1 positive surgical margins. Table 2.6. The stage, grade and preoperative PSA group for the unmatched patients. Table 3.1. Details of microsatellite markers. Table 4.1. Overall results - all patients. Table 4.2. Overall results - relapse group. Table 4.3. Overall results - non-relapse group. Table 4.4. Summary: rate of AI in relapse and non-relapse groups. Table 4.5. Status of 30 microsatellite loci in 31 matched pairs of radical prostatectomy patients with pT3N0 stage disease. Table 4.6. Incidence of microsatellite instability in the relapse and non-relapse groups. Table 5.1. Intragenic primers for p21 WAF1/C1PI and GAPDH. Table 5.2. PCR master mix for lx 50pl reaction. Table 5.3. p21 WAFI/CIPI primers. 8 Table 5.4. Results o f p 2 JlVAf,CIPI promoter sequencing after sodium bisulphite DNA modification. Figure 1.1. Prostate cancer age-specific incidence in Great Britain (1979-2001). Figure 1.2. Genetic changes underlying the initiation and progression of prostate cancer. Figure 1.3. The Gleason grading system of prostate cancer. Figure 1.4 a) Low power of radical prostatectomy wholemount section demonstrating organ confined prostate cancer, b) an intraprostatic positive surgical margin, c) extraprostatic carcinoma with a positive surgical margin. Figure 1.5. Time to develop PSA recurrence (PSA >2) after adjuvant radiotherapy and salvage radiotherapy with a pre-treatment PSA <1 .Ong/ml and >1 .Ong/ml. Figure 1.6. The androgen receptor ligands and androgen responsive element. Figure 1.7. Demonstrates locus ‘a’ in a normal cell and a malignant cell containing microsatellite instability and allelic imbalance (LOH). Figure 2.1. Pathological stage over time in the UCL Radical Prostatectomy database. Figure 2.2. Assessment of margin status using the shave technique. Figure 3.1 a) Coronal block of prostate embedded in paraffin, b) master slide with area of prostate containing at least 70% malignant cells marked, c) 10pm section unstained, d) section stained, tumour area marked and excised with scalpel blade. Figure 3.2. Laser capture microdissection a) area of tumour marked, b) tumour captured on polymerised film, c) defect left on slide. Figure 3.3. Agarose gel of primer D7S523 at 2.5, 5 and 8 picomoles per 15pl reaction in DNA from unmatched patients. Figure 3.4. Agarose gel showing optimisation with DNA from 8 unmatched patients at marker D10S211. Figure 3.4. The electrophoresis circuit. Figure 3.5. Allelic imbalance is present where the amplitude of the smaller cancer peak divided by the larger cancer peak over the amplitude of the smaller control peak divided by the larger control peak is 0.7 or less. Figure 4.1. Shows characteristic cancer and control electropherograms for 5 markers, demonstrating stutter peaks preceding the
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