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Table of Contents Table of Contents Table of contents Table of contents................................................................................................................. 1 Summary ............................................................................................................................. 3 Abbreviations ...................................................................................................................... 4 Gene Symbols I - Incidentals .............................................................................................. 5 Gene symbols II - Target Gene Names ............................................................................... 6 1. Introduction........................................................................................................... 12 1.1. The Pathos of the Crab ..................................................................................... 12 1.2. Cancer in the Molecular Age - a genetic and epigenetic disease..................... 13 1.3. Tumoral evolution............................................................................................. 14 1.4. DNA repair systems .......................................................................................... 17 1.4.1. DNA Mismatch Repair.............................................................................. 18 1.4.2. Double-strand Break Repair..................................................................... 19 1.4.3. Direct Repair............................................................................................ 21 1.4.4. Nucleotide Excision Repair.......................................................................21 1.4.5. Base Excision Repair ................................................................................ 21 1.5. The Cell Cycle and Apoptosis........................................................................... 22 1.6. Mutator Phenotypes.......................................................................................... 25 1.7. Colorectal cancer.............................................................................................. 25 1.7.1. Signaling pathways critical to colorectal carcinogenesis ........................ 30 1.7.2. Colorectal cancer with microsatellite instability...................................... 35 1.7.2.1 MMR deficiency and replication slippage ................................................ 35 1.7.2.2. Other non-slippage-induced alterations in MSI tumors .......................... 36 1.7.2.3. Concepts of downstream MSI target genes.............................................. 36 1.7.2.4. Nonsense-mediated decay and immunogenicity in MSI cancers ............. 39 1.8. Objectives.......................................................................................................... 40 2. Materials and Methods ......................................................................................... 41 2.1. Materials........................................................................................................... 41 2.1.1. MSI series..................................................................................................41 2.1.2. AUS series................................................................................................. 41 2.1.3. Cell lines................................................................................................... 41 2.2. Methods............................................................................................................. 42 2.2.1. DNA isolation............................................................................................42 2.2.2. MSI status..................................................................................................42 2.2.3. Literature survey of putative target genes ................................................ 44 2.2.4. Target genes.............................................................................................. 46 2.2.4.1. Target gene selection ............................................................................... 46 2.2.4.2. Mutation analysis..................................................................................... 49 2.2.4.3. Clustering analysis and survival correlation of target genes.................. 53 2.2.4.4. In silico assessment of frameshift consequences ..................................... 54 3. Results....................................................................................................................... 55 3.1. MSI series..........................................................................................................55 3.1.1. MSI status..................................................................................................55 3.1.2 Literature survey....................................................................................... 56 3.1.3. Target gene mutation................................................................................ 61 1 3.2. AUS series......................................................................................................... 68 3.2.1. DNA quantity and quality ......................................................................... 68 3.2.2. MSI status – AUS series............................................................................ 68 4. Discussion................................................................................................................. 69 Perspectives .................................................................................................................. 75 Reference List.................................................................................................................... 76 Appendix 1 - Analysis of MSI status in MSI series and AUS series…………………………… Appendix 2 - Mutation analyses of MSI target genes…………………………………………… Appendix 3 - Primer sequences for Bethesda markers and MSI target genes……………… Appendix 4 - Reference List for Table 2: Literature Survey…………………………………… Appendix 5 - PCR conditions for Bethesda marker MSI-testing……………………………… Appendix 6 - Review of MSI target genes………………………………………………………… 2 Summary Colorectal cancer is one of the most common cancer types, and a leading cause of cancer-related deaths. Cases can be divided into two main molecular phenotypes: those with chromosomal instability (CIN) and those with microsatellite instability (MSI), which occur at a frequency of 85% and 15%, respectively. The focus of this study was on MSI tumors, which have defective mismatch repair systems, and on the multitudinous insertions and deletions in MSI tumor DNA which are the result of this defect. The primary aim of the thesis was to serve as a pilot project for later work on a consecutive, clinically representative tumor series. Firstly, we wished to establish an assemblage of genes which could reasonably be assumed to be targets of mismatch repair deficiency, i.e. that they were more frequently subject to insertions or deletions than comparable sequences. Secondly, we wanted to see whether there were, among the above targets, genes which either singly or in company appeared to affect patient outcome depending on their mutational status. A search of the available scientific literature for genes which had been analyzed for, almost uniquely, frameshift mutations in MSI tumors yielded 162 candidates. Forty- three of these were selected for laboratory analysis. The results provided confirmation of the target gene status for many of these, among them certain well-known genes such as TGFβRII, MSH3, E2F4 and CASP5. The histone acetyl transferase EP300 had never before been examined for this type of mutation in primary tumor DNA, and proved to be a low-frequency, but nevertheless noteworthy, target in MSI colorectal cancers. No significant covariance of genes was found which did not depend on mutation frequency alone. A single gene of intermediate mutation frequency showed a robust association with long- term patient survival. SLC23A2, which encodes a sodium/vitamin C cotransporter, was significantly associated with poor prognosis when mutated, and showed indications of being additionally informative with regard to clinical staging as well. 3 Abbreviations ATP Adenosine triphosphate BER Base excision repair CDK Cyclin-dependent kinase CIMP CpG island methylator phenotype CIN Chromomsomal instability CML Chronic myelogenous leukemia cMNR Coding mononucleotide repeat CpG Cytosine-phosphate-guanine CRC Colorectal cancer CSC Cancer stem cell DNA Deoxyribonucleic acid GEF Guanine nucleotide exchange factor GJIC Gap junction intercellular communication HNPCC Hereditary non-polyposis coli MMR Mismatch repair MSI Microsatellite instability MSI-H High microsatellite instability MSI-L Low microsatellite instability MSS Microsatellite stability NER Nucleotide excision repair NHEJ Non-homologous end joining NMD Nonsense-mediated decay PCR Polymerase chain reaction RNA Ribonucleic acid UTR Untranslated region 4 Gene Symbols I - Incidentals ABL Abelson murine leukemia viral (v-abl) oncogene homolog AKT Protein kinase B APC Adenomatous polyposis coli APE Apurinic/apyrimidinic endonuclease ARF Alternative reading frame = p14 BCL2 B-cell chronic lymphatic leukemia/lymphoma 2 BCR Breakpoint cluster region BECN1 Beclin 1 BIRC5 Baculoviral IAP repeat-containing protein 5 BRAF v-raf murine sarcoma viral oncogene homolog B1 BRCA1 Breast cancer gene 1 CCND1 Cyclin D1 CDH1 E-cadherin CTNNB β-catenin ERCC1 Excision repair cross-complementing rodent repair deficiency, complementation
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