Epigenetic alterations in sporadic and familial cancers

10 INTRODUCTION 12 REVIEW OF THE LITERATURE 13 1 Epigenetics overview 13 1.1 DNA methylation 14 1.2 Post-translational histone modifications and chromatin remodeling 16 1.3 Noncoding RNAs and RNA interference 17 1.4 Interplay between different epigenetic factors 18 1.5 Epigenetic inheritance 19 2 Basic characteristics of cancer 20 3 Cancer genetics 23 3.1 Tumor suppressor genes 23 3.2 Oncogenes 25 3.3 Genomic instability 26 3.3.1 Chromosomal instability and loss of heterozygosity 27 3.3.2 Microsatellite instability 28 3.3.2.1 Mismatch repair (MMR) pathway 29 3.4 Colorectal cancer 30 3.4.1 Hereditary non-polyposis colorectal cancer syndrome (HNPCC) 33 3.4.2 Lynch syndrome (LS) 34 3.4.3 Familial colorectal cancer type X (FCCX) 35 3.5 Endometrial cancer 36 3.5.1 Lynch syndrome associated endometrial cancer 37 3.5.2 Familial site-specific endometrial cancer (FSSEC) 38 3.6 Gastric cancer 38 4 Cancer epigenetics 39 4.1 DNA hypermethylation in cancer 39 4.2 DNA hypomethylation in cancer 40 4.3 Other epigenetic events in cancer 41 AIMS OF THE STUDY 43 MATERIALS & METHODS 44 1 Patients and samples 44 2 Genomic mutation, microsatellite instability and loss of heterozygosity analyses 46 3 DNA methylation analyses 47 4 Protein expression analyses 50 5 Statistical analyses 50 RESULTS 51 1 DNA hypermethylation in cancer (I, II) 51 1.1 Shared and tissue-specific tumor suppressor gene methylation patterns 52 1.2 DNA methylation patterns in separate patient categories – dependence of methylation patterns on the MSI status and the familial background of cancer 54 1.3 CpG island methylator phenotype as a driver of tumorigenesis? 55 2 Global genomic hypomethylation in cancer (III) 55 3 Changes in methyltransferase activity in cancer (IV) 57 3.1 Aberrant DNA methylation – aberrant methyltransferase patterns? 57 3.2 Looking for underlying causes for methyltransferase protein overexpression 59 DISCUSSION 60 1 DNA methylation in colorectal, endometrial and gastric cancers 60 1.1 DNA methylation patterns as tumor classifiers 60 1.2 Methodological aspects 62 2 Elucidating the background of methylation changes 63 3 Overall conclusions of the findings 65 CONCLUSIONS & FUTURE PROSPECTS 68 ACKNOWLEDGEMENTS 72