Title Page

ABSTRACT

Contents

List of Abbreviations 19

Chapter 1. Background and Literature Review of Study 21

1.1. Incidence and Aetiology of CRC 22

1.1.1. Epidemiological Trends in CRC 22

1.1.2. Modifiable Risk Factors 25

1.1.3. Genetic Factors 28

1.2. Carcinogenic Pathway and Molecular Subtype of CRC 30

1.2.1. Colorectal Carcinogenesis Phase and Pathway 30

1.2.2. Classification of Molecular Subtype 33

1.3. Methyl Donor Nutrients (One-carbon Metabolism) and CRC 38

1.4. DNA Mismatch Repair Machinery and Microsatellite Instability (MSI) on CRC 60

1.5. A Machine Learning Approach and CRC 70

1.6. Purpose of Study 80

Chapter 2. Dietary Methyl Donor Nutrients and Modifiable Lifestyle Factors on CRC Risk 83

2.1. Introduction 84

2.2. Subjects and Methods 86

2.2.1. Study Population 86

2.2.2. Clinicopathological Data Collection 87

2.2.3. Microsatellite Instability and DNA Mismatch Repair Proteins(MSI-MMR) Status 89

2.2.4. Assessment of Dietary Methyl Donor Nutrients 89

2.2.5. Assessment of Modifiable Lifestyle Factors 90

2.2.6. Statistical Analysis 91

2.3. Results 92

2.3.1. General Characteristics of Study Subjects 92

2.3.2. Clinicopathological Feature of CRC Patients 94

2.3.3. Comparison of Dietary Methyl Donor Nutrient Intake 96

2.3.4. Association between Dietary Methyl Donor Nutrients and CRC Risk by Anatomic Subsite and MSI-MMR Status 98

2.3.5. Comparison of Contributing Food in Methyl Donor Nutrients 107

2.3.6. Association between Modifiable Lifestyle Factors and CRC Risk by Anatomic Subsite and MSI-MMR Status 115

2.3.7. Spearman's Correlation Coefficient of Methyl Donor Nutrients and Modifiable Lifestyle Factors 118

2.3.8. Association between Dietary Methyl Donor Nutrients and CRC Risk by Modifiable Lifestyle Factors 121

2.4. Discussion 131

2.5. Conclusions 136

Chapter 3. Interaction among Dietary Methyl Donor Nutrients, Modifiable Lifestyle Factors, and Common Polymorphisms of DNA Mismatch Repair Genes on CRC Risk 137

3.1. Introduction 138

3.2. Materials and Methods 141

3.2.1. SNP Genotyping 141

3.2.2. Selection of Candidate Polymorphisms on DNA MMR Genes 143

3.2.3. Statistical Analysis 145

3.3. Result 147

3.3.1. Haplotype Distribution and Tagging SNPs in DNA MMR Genes for Association with CRC Risk 147

3.3.2. Association between Candidate Polymorphisms of hMSH3 Gene and CRC Risk 153

3.3.3. Association between Candidate Polymorphisms of hMSH3 Gene and CRC Risk by Anatomic Subsite and MSI-MMR Status 155

3.3.4. Association between Candidate Polymorphisms of hMSH3 Gene and CRC Risk according to Family History of CRC 157

3.3.5. Comparison of Functional Annotation in Candidate Polymorphisms of hMSH3 Gene 159

3.3.6. Interaction between Dietary Methyl Donor Nutrients and Candidate Polymorphisms of hMSH3 Gene on CRC Risk 161

3.3.7. Interaction between Dietary Niacin Intake and hMSH3 rs41097 Polymorphism on CRC Risk by Anatomic Subsite and MSI-MMR Status 166

3.3.8. Interaction between Dietary Niacin Intake and hMSH3 rs41097 Polymorphism on CRC Risk by Modifiable Lifestyle Factors 168

3.4. Discussion 171

3.5. Conclusions 178

Chapter 4. Impact of Dietary Methyl Donor Nutrients, Modifiable Lifestyle Factors, and DNA Mismatch Repair Genes for Prediction of CRC Using a Machine Learning Approach 179

4.1. Introduction 180

4.2. Materials and Methods 183

4.2.1. Dataset and Pre-processing 183

4.2.2. Construction of Machine Learning Models 186

4.2.3. Model Assessment 188

4.3. Results 190

4.3.1. Comparison of Confusion Matrix for Machine Learning Models 190

4.3.2. Identification of the Importance Feature from Machine learning Models 194

4.4. Discussion 197

4.5. Conclusions 202

Chapter 5. Concluding Remarks 203

5.1. Summary of Study 204

5.2. Limitation of Study 206

5.3. Significance and Future Study 207

BIBLIOGRAPHY 210

Appendices 241

Appendix-1. Flow chart of study subjects for interaction analysis 241

Appendix-2. Description of all polymorphisms on DNA MMR genes 242

Appendix-3. Interaction between modifiable lifestyle factors and candidate polymorphisms of hMSH3 gene on CRC risk 250

Appendix-4. Forms of the written informed consent 254

Appendix-5. The approval by the institutional review board of the National Cancer Center 258

Appendix-6. A structured general questionnaire provided to the case group 261

Appendix-7. A structured general questionnaire provided to the control group 270

Appendix-8. A semi-quantitative food frequency questionnaire (SQFFQ) provided to the case and control groups 281

Table 1-1. Hereditary CRC syndrome and genes 29

Table 1-2. Literature review of the association between dietary methyl donor nutrients and CRC risk 42

Table 1-3. Description of DNA MMR genes 61

Table 1-4. Literature review of the association among MMR genes, MSI status, and CRC risk 65

Table 1-5. Literature review of the association among environmental factors, MMR genes, and MSI status on CRC risk 67

Table 1-6. Literature review of machine learning techniques applied to detection and classification of CRC 74

Table 2-1. General characteristics of study subjects 93

Table 2-2. Clinicopathological feature of CRC patients 95

Table 2-3. Comparison of dietary methyl donor nutrient intake 97

Table 2-4. Association between dietary methyl donor nutrient intake and CRC risk by anatomic subsite and MSI-MMR status 100

Table 2-5. Comparison of contributing food in methyl donor nutrients 108

Table 2-6. Association between modifiable lifestyle factors and CRC risk by anatomic subsite and MSI-MMR status 117

Table 2-7. Spearman's correlation coefficient of methyl donor nutrients and modifiable lifestyle factors 119

Table 2-8. Association between dietary methyl donor nutrient intake and CRC risk by modifiable lifestyle factors 124

Table 3-1. Description of Tag SNPs in DNA MMR genes and FDR analysis for... 152

Table 3-2. Association between candidate polymorphisms of hMSH3 gene and CRC risk 154

Table 3-3. Association between candidate polymorphisms of hMSH3 gene and CRC risk by anatomic subsite and MSI-MMR status 156

Table 3-4. Association between candidate polymorphisms of hMSH3 gene and CRC risk according to family history of CRC 158

Table 3-5. Comparison of functional annotation in candidate polymorphisms of hMSH3 gene 160

Table 3-6. Interaction between dietary methyl donor nutrient intake and candidate polymorphisms of hMSH3 gene on CRC risk 162

Table 3-7. Interaction between dietary niacin intake and hMSH3 rs41097 polymorphism on CRC risk by anatomic subsite and MSI-MMR status 167

Table 3-8. Interaction between niacin intake and hMSH3 rs41097 polymorphism on CRC risk by modifiable lifestyle factors 169

Table 4-1. Description of feature variables in the study for a machine learning approach 185

Table 4-2. Comparison of a confusion matrix for each model 191

Figure 1-1. Age-standardized incidence (A: men, B: women)... 23

Figure 1-2. The proportion of CRC case 24

Figure 1-3. Colorectal carcinogenesis phase and pathway 32

Figure 1-4. Comparison between traditional and currently proposed classification of... 36

Figure 1-5. Molecular pathway in colorectal tumorigenesis 37

Figure 1-6. Overview of one-carbon metabolism 41

Figure 1-7. Schematic diagram of DNA MMR and MSI pathway 64

Figure 1-8. Artificial intelligence, machine learning, and deep learning 71

Figure 1-9. The workflow of a machine learning approach 72

Figure 1-10. Construction of study 82

Figure 2-1. Flow chart of study subjects 88

Figure 3-1. Flow chart of the selection procedure for candidate polymorphisms... 142

Figure 3-2. LocusZoom plot of all polymorphisms on DNA MMR genes 144

Figure 3-3. A haplotype of DNA MMR polymorphisms and Tag SNPs. 149

Figure 4-1. Schematic workflow of a machine learning approach... 184

Figure 4-2. Receiver operating characteristic (ROC) area under the curve... 192

Figure 4-3. Feature importance of each model 195