Genetics of Colorectal Cancer (eBook)

Contents 6
Introduction 11
Part I: Epidemiology and Models of Colorectal Cancer 13
Chapter 1 14
Colorectal Cancer: Epidemiology 14
Introduction 14
Descriptive Epidemiology 14
Genetic and Molecular Events in Colorectal Cancer 15
Environmental Risk Factors 16
Diet 16
Vegetables, Fruits, Fiber, and Micronutrients 16
Meat 19
Total Dietary Fat 20
Animal or Saturated Fat 20
Calcium and Vitamin D 20
Physical Activity and Anthropometry 21
Alcohol 22
Tobacco 22
Reproductive Factors 23
Infection 23
Occupation 24
Medical Conditions 24
Inflammatory Bowel Disease 24
Diabetes Mellitus 24
Cholecystectomy 25
Medications 25
NSAIDs 25
Postmenopausal Hormone Use 26
Conclusion 26
References 27
Chapter 2 35
Mouse Models of Intestinal Cancer 35
Introduction 35
GEM and the Wnt Signaling Pathway 35
Min/+ and Related Mice 35
beta-Catenin Transgenic Mice 38
Genes that Modify the Wnt Pathway 39
GEM and the TGFbeta Signaling Pathway 40
TGFbeta1 / and Related Mice 40
Smad / Mice 41
GEM and DNA Mismatch Repair 42
Immune-Deficient GEM 44
Cytokine-Deficient Mice 45
Mucin-Deficient Mice 45
Carcinogen-Induced Models of Intestinal Tumorigenesis 46
Other GEM Models of Intestinal Cancer 47
RbMI/MI Mice 47
PI(3)K-Deficient Mice 47
Cdx2 / Mice 48
Dominant Negative N-Cadherin Mice 48
Conclusions 48
References 49
Part II: Pathways to Colorectal Cancer 58
Chapter 3 59
The Chromosomal-Instability Pathway and APC Gene Mutation in Colorectal Cancer 59
Introduction 59
Evidence for the Existence of a Chromosomal-Instability Pathway 60
The Genetic Basis of the Chromosomal-Instability Pathway 62
APC Mutation and Chromosomal Instability 66
Conclusions 73
References 74
Chapter 4 79
DNA Methylation in Colorectal Cancer: Multiple Facets of Tumorigenesis 79
Introduction 79
DNA Methylation and Neoplasia 81
Epigenetic Changes in Colorectal Neoplasia 83
Genome-Wide Hypomethylation of DNA 83
Loss of Imprinting in Colorectal Cancer 85
Polycomb Proteins and DNA Methylation in Colorectal Cancer 85
The CpG-Island Methylator Phenotype 87
The Histological Context of CIMP in the Colorectum 90
Epidemiology of CIMP in Colorectal Neoplasia 91
Rare Events: Germline Epimutation and Colorectal Cancer 92
DNA Methylation in the Diagnosis and Therapy of Cancer 93
Conclusions 94
References 94
Chapter 5 102
Pathways and Pathology 102
Introduction 102
Adenoma-Carcinoma Sequence 102
Malignant Potential of Adenomas in Different Clinical Scenarios 103
Adenoma Multiplicity and Malignant Potential 104
Mechanisms Underlying the Initiation of Colorectal Adenomas 105
Lack of Equivalence of FAP Versus Sporadic Micro-Adenomas 107
Precursor Lesions for Sporadic Colorectal Cancer that Are Not Well Represented in FAP 109
Villous Adenoma 110
Serrated Adenoma 111
Hyperplastic Polyps and Allied Lesions with Malignant Potential 113
Colorectal Cancer: A Multi-pathway Disease 116
‘Fusion Polyps’ and ‘Fusion Pathways’ for the Accelerated Evolution of Colorectal Cancer 118
Conclusion 120
References 121
Part III: Germline Susceptibility – Mendelian and Other Syndromes 127
Chapter 6 128
Familial Adenomatous Polyposis 128
Introduction 128
Clinical Summary of FAP 128
Epidemiology 128
Clinical Presentation 129
Gastric Polyps 129
Duodenal Polyps 130
Desmoid Tumors 130
Osteomas and Dental Abnormalities 131
Congenital Hypertrophy of Retinal Pigment Epithelium 131
Thyroid Carcinoma 132
Adrenal and Hepatobiliary Tumors 132
Attenuated FAP 132
Genetics of FAP 133
APC and FAP 133
APC Germline Mutations Leading to FAP 134
Genotype–Phenotype Association: Polyposis Severity 135
Genotype–Phenotype Association: Extracolonic Manifestations of FAP 136
APC Polymorphisms 137
FAP Modifier Genes 137
Non-APC-Associated Polyposis 138
References 138
Chapter 7 143
DNA Mismatch Repair and Lynch Syndrome 143
Introduction 143
Genomic Instability 143
DNA Mismatch-Repair Mechanism 144
Gene Discovery 145
Microsatellite Instability 146
Molecular Screening for Lynch Syndrome 147
Mutation Profile 150
Large Genomic Rearrangements 150
Missense Mutations 152
Founder Mutations 154
Heritable Epimutations? 155
Evolution of a Name: HNPCC Versus Lynch Syndrome 157
Incidence 158
Histopathology 159
Clinical Features 161
Tumor Spectrum 161
Penetrance 162
Clinical Variants of Lynch Syndrome 162
References 163
Chapter 8 172
Additional Syndromes with Hereditary Predisposition to Colorectal Cancer 172
Chapter 8.1 173
MUTYH-Associated Polyposis 173
Introduction 173
Base-Excision Repair and MUTYH 173
MAP Cancer Development 174
Clinical Features 175
Cancer Risk to Heterozygotes 177
Conclusion 178
References 178
Chapter 9 182
Familial Colorectal Cancer Type X 182
References 185
Chapter 10 186
Families with Serrated Neoplasia of the Colon 186
Introduction 186
Hyperplastic Polyposis Syndrome 187
Phenotypic Dichotomy in Hyperplastic Polyposis Syndrome 188
Serrated Pathway Syndrome 188
Conclusion 188
References 189
Chapter 11 191
Peutz–Jeghers Syndrome 191
Background 191
Manifestations 191
STK11 192
Functions of STK11 192
Mouse Model 193
Carcinogenesis in PJS 193
STK11 Loss of Heterozygosity and Somatic Mutations in Sporadic Cancer 194
Cyclooxygenase-2 194
References 194
Chapter 12 197
Juvenile Polyposis 197
References 202
Chapter 13 204
BLM Mutation and Colorectal Cancer Susceptibility 204
Bloom Syndrome and the BLM Gene 204
Biochemical Properties of BLM 205
Blm/BLM Mutation and Colorectal Cancer Susceptibility 206
References 207
Chapter 14 210
The Role of p53 in Colorectal Cancer 210
References 213
Chapter 15 215
Chromosomes 8q24 and 9p24: Associations with Colorectal Cancer 215
References 216
Part IV: Germline Susceptibility –Gene-Environment Interactions 217
Chapter 16 218
Genetic Variability in Folate-Mediated One-Carbon Metabolism and Risk of Colorectal Neoplasia 218
Introduction 218
Investigating Genetic Polymorphisms in Epidemiologic Studies 219
Polymorphisms in One-Carbon Metabolism and Their Functional Impact 220
Thymidylate Synthase 220
5,10-Methylenetetrahydrofolate Reductase 221
Methionine Synthase 222
Methionine Synthase Reductase 222
Serine Hydroxymethyltransferase 222
Cystathionine beta -Synthase 223
Reduced Folate Carrier 223
Other Genes 224
Polymorphisms in One-Carbon Metabolism and Colorectal Cancer Risk 224
5,10-Methylenetetrahydrofolate Reductase 225
Thymidylate Synthase 226
Methionine Synthase 227
Methionine Synthase Reductase 228
Other Genes 228
Final Thoughts 229
References 229
Chapter 17 238
Genetic Variability in NSAID Targets and NSAID-Metabolizing Enzymes and Colorectal Neoplasia 238
Introduction 238
Genetic Variability in NSAID Targets 239
Cyclooxygenase-1 (COX-1) 240
Cyclooxygenase-2 (COX-2) 240
Other Targets 240
Ornithine Decarboxylase 242
Genetic Variability in NSAID-Metabolizing Enzymes 243
UGT1A6 243
CYP2C9 243
Genetic Variability in NSAID Targets and NSAID-Metabolizing Enzymes and Risk of Colorectal Neoplasia 244
NSAID Targets 244
COX-1 244
COX-2 245
Other Genes Related to Prostaglandin Synthesis 246
ODC1 247
NSAID-Metabolizing Enzymes 247
UGT1A6 247
CYP2C9 248
Summary 249
References 249
Chapter 18 256
The Role of Chemical Carcinogens and Their Biotransformation in Colorectal Cancer 256
Chemical Carcinogens 257
Heterocyclic Aromatic Amines 257
Polycyclic Aromatic Hydrocarbons 257
Nitrosamines 258
Acrylamide 258
Biotransformation 259
Heterocyclic Amines 260
Polycyclic Hydrocarbons 260
N-Nitroso Compounds 260
Modulators of Biotransformation 261
Environmental Modulators 261
Genetic Modulators 262
Genetic Polymorphisms in Biotransformation Genes and CRC Risk 263
Conclusion and Research Needs 265
References 266
Chapter 19 272
Calcium and Vitamin D 272
Introduction 272
Calcium and Vitamin D Physiology and Metabolism 272
Calcium 272
Vitamin D 273
Mechanisms of Calcium and Vitamin D in Colorectal Carcinogenesis 275
Calcium 275
Bile Acids 276
Direct Effect on Cell Cycle 276
Calcium and the CaSR 276
Vitamin D 277
Bile Acids 277
Direct Effect on Cell Cycle 277
Growth-Factor Signaling 277
Immunomodulation 278
Epidemiology of Calcium, Vitamin D, and Colorectal Neoplasms 278
Calcium 279
Observational Studies of Colorectal Cancer and Calcium 279
Observational Studies of Colorectal Adenoma and Calcium 279
Calcium and Clinical Trials of Biomarkers 280
Calcium and Clinical Trials of Colorectal Neoplasms 280
Observational Studies of CaSR Gene Polymorphisms and Colorectal Neoplasms 281
Studies of Calcium in Interaction with Other Agents, Risk Factors, and Genotypes in Relation to Risk of Colorectal Neoplasms 281
Vitamin D 283
Observational Studies of Colorectal Cancer and Vitamin D 283
Observational Studies of Colorectal Adenoma and Vitamin D as a Main Effect 284
Observational Studies of Colorectal Neoplasms and VDR and Vitamin D-Metabolizing Enzyme Gene Polymorphisms 285
Studies of Colorectal Neoplasms and Vitamin D and VDR Genotypes and Their Interaction with Other Genotypes 286
Calcium Plus Vitamin D 287
Overall Summary and Conclusions 288
References 289
Index 294
Contributors 8