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Identification of the Genetic Alterations in Prostate Cancer Metastases

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Identification of the Genetic Alterations in Prostate Cancer Metastases Identification of the genetic alterations in prostate cancer metastases Elzbieta Stankiewicz Submitted in partial fulfilment of the requirements of the Degree of Doctor of Philosophy Supervisor: Dr Yong-Jie Lu and Prof D. Berney Molecular Oncology and Imaging Barts Cancer Institute Queen Mary University of London John Vane Science Centre Charterhouse Square London EC1M 6BQ 1 STATEMENT OF ORIGINALITY I, Elzbieta Stankiewicz, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below and my contribution indicated. Mrs Tracy Chaplin provided help with the hybridisation, staining and scanning of Affymetrix SNP array. Dr. Xueying Mao helped me with SNP data analysis and FISH methodology. Dr. Marc Yeste-Velasco helped me with generation of stable 22RV1 shFBXL4 cells. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: Elzbieta Stankewicz Date: 30.06.16 2 ACKNOWLEDGEMENTS I would like to thank my supervisors, Dr. Yong-Jie Lu and Prof Dan Berney for giving me the opportunity to do this PhD and for all their support, patience and guidance without which I would not be able to complete my dissertation. I would also like to thank all my colleagues in Barts Cancer Institute that advised, helped and supported me through my PhD. This work was supported by the ORCHID charity. 3 Abstract Prostate cancer (PCa) is the most common cancer among men in Western developed countries. While the majority of PCa diagnosed by PSA screening are indolent, advanced and metastatic disease has a significant mortality and morbidity. Bone metastases are extremely common in PCa and identification of bone metastasis associated genes may provide insights into PCa progression and assist in finding new drug targets. However, the genetic study of bone metastases is very limited due to the difficulty of sampling. We performed genome-wide analysis of six fresh frozen PCa bone metastases. We found several alterations commonly present in advanced PCa, including gains at: 1q32.1, broad gains of 8q (MYC, NCOA2), 9q33.2-34.3, 11q13.1-14.1 (CCND1), 12q24.23- 24.31, 16p13.3, 16p12.1-11.2 and Xq12-13.1 (AR) as well as losses at: 5q11.1-22.1, 5q14.3-23.1, 6q14.1-22, 8p23.2-p21, 13q13.2-31.1 (RB1), 17p13.1-12 (TP53) and 18q11.1-22.3. Two cases also showed PTEN loss and one sample had deletion indicative of TMPRSS2-ERG fusion. For downstream analysis we concentrated on CCND1 oncogene at 11q13 and FBXL4 at 6q16 as potential drivers of these genomic changes. Using fluorescence in situ hybridisation we found common CCND1 gain and FBXL4 loss in PCa bone metastases (54.5%, 12/22 and 47.8%, 11/23, respectively), much less frequent in primary tumours (7%, 10/142 and 13.8%, 20/145, respectively) and absent in BPH cases (0/55). The expression levels of cyclin D1 protein, coded by CCND1 correlated with CCND1 copy number gain (p < 0.0001) and were higher in metastatic tumours than in primary PCa (p = 0.015), confirming cyclin D1 involvement in advanced PCa. Presence of FBXL4 loss in early stage primary PCa strongly correlated with current PCa prognostic markers and with worse patient survival. Therefore, we propose that FBXL4 may be a tumour suppressor gene in prostate, whose loss in early PCa could be indicative of more aggressive disease. Using in vitro experiments we demonstrated that FBXL4 regulates cells motility and invasion. We confirmed that ERLEC1, an ER lectin involved in ER stress response pathway is a degradation target of FBXL4. As activation of ER stress response pathway is linked to enhanced cell migration and invasion, loss of FBXL4 could be one of the mechanisms by which cancer cells increase their efficiency to respond to stress and to escalate their metastatic potential through stabilisation of ERLEC1. Further studies of FBXL4 – ERLEC1 axis are necessary to establish how they contribute to PCa progression. This knowledge can potentially help to develop novel targeted therapies for aggressive disease harbouring FBXL4 abnormalities. 4 ABBREVIATIONS ADT Androgen deprivation therapy AR Androgen receptor BAC Bacterial artificial chromosomes bp Base pair BPH Benign prostatic hyperplasia BSA Bovine serum albumin cDNA Complementary deoxyribonucleic acid CGH Comparative genomic hybridisation CIN Chromosome instability CAN Copy number alteration CNV Copy number variation CRL Cullin-RING E3 ubiquitin ligases CRPC Castration resistant prostate cancer DAPI 4,6-diamidino-2-phenylindole dihydrochloride DEPC Diethylpyrocarbonate, inactivates RNase enzymes DHT Dihydrotestosterone DIG Digoxigenin DMEM Eagle's minimal essential medium DMSO Dimethyl sulphoxide DNA Deoxyribonucleic acid dNTP Deoxyribonucleotide triphosphate DRE Digital rectal examination DPX Di-n-butyle phthalate in xylene DTT Dithiothreitol EB Tris/HCl EMT Epithelial-mesenchymal transition 5 ER Endoplasmic reticulum ERAD Endoplasmic reticulum associated degradation FAM Carboxyfluorescein FCS Foetal Calf Serum FFPE Formalin-Fixed, Paraffin-Embedded FISH Fluorescence in situ hybridisation GOLF Genome Oriented Laboratory File system GWAS Genome-wide association study H&E Hematoxylin and eosin HGPIN High grade prostatic intraepithelial neoplasia IF Immunofluorescence IHC Immunohistochemistry Kb Kilobase LB Lysogeny broth LNM Lymph node metastasis LOH Loss of heterozygosity MAD Mitochondria associated degradation mCRPC Metastatic castration resistant prostate cancer MIN/MSI Microsatellite instability mRNA Messenger RNA MOR Minimal overlapping region NaCl Sodium chloride PBS Phosphate-buffered saline PCa Prostate cancer PCR Polymerase chain reaction PIN Prostatic intraepithelial neoplasia PSA Prostate-specific antigen 6 qPCR Quantitative PCR RNA Ribonucleic acid rpm Revolutions per minutes RPMI Roswell Park Memorial Institute medium SCF Skp, Cullin, F-box containing ubiquitin ligases shRNA Small hairpin Ribonucleic Acid siRNA Small interfering Ribonucleic Acid SNP Single nucleotide polymorphism SSC Sodium chloride sodium citrate TAPG Transatlantic Prostate Group TBE Tris/Borate/EDTA TE Tris/EDTA TMA Tissue microarray TNM Staging System: T-primary tumour, N- number of involved lymph nodes, M-metastasis TSG Tumour suppressor gene TURP Transurethral resection of the prostate UPR Unfolded protein response UTP Uridine 5'-triphosphate V Volt WB Western blot 7 TABLE OF CONTENT STATEMENT OF ORIGINALITY ........................................................................ 2 ABBREVIATIONS .............................................................................................. 5 LIST OF TABLES ............................................................................................. 16 1 INTRODUCTION AND AIMS ................................................................. 20 1.1 PROSTATE CANCER .................................................................................... 20 1.1.1 The prostate anatomy and origin of prostate cancer ..................................... 20 1.1.2 Prostate cancer incidence, mortality and survival ......................................... 21 1.1.3 Risk factors ................................................................................................... 22 1.1.4 Role of androgen in PCa .............................................................................. 22 1.1.5 Prostate cancer screening using PSA ........................................................... 23 1.1.6 Gleason grading system ............................................................................... 24 1.1.7 Staging of prostate cancer ............................................................................ 26 1.1.8 PCa treatment .............................................................................................. 27 1.1.8.1 Localised low-risk indolent prostate cancer .................................................................... 28 1.1.8.2 High-risk prostate cancer ................................................................................................ 28 1.2 GENETIC ALTERATION IN PROSTATE CANCER ........................................ 29 1.2.1 Genomic instability and cancer ..................................................................... 29 1.2.2 Prostate cancer susceptibility genes ............................................................. 31 1.2.3 Somatic genetic changes in prostate cancer ................................................. 33 1.3 METASTATIC PROSTATE CANCER ............................................................. 38 1.3.1 Mechanism of metastasis ............................................................................. 38 1.3.2 Bone metastases .......................................................................................... 41 1.3.2.1 Normal bone physiology.................................................................................................. 42 1.3.2.2 Types of bone metastases
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