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Title Page

Abstract

Contents

List of abbreviations 19

I. Introduction 21

I.1. Background 21

I.1.1. Breast cancer statistics 21

I.1.2. Heterogeneity of breast cancer 22

I.1.3. Previous studies on distribution of intrinsic subtypes 26

I.1.4. Previous studies on risk factors of breast cancer by intrinsic subtypes 26

I.1.5. Previous studies on prognostic factors of breast cancer by intrinsic subtypes 38

I.2. Hypothesis and objectives 41

I.2.1. Hypothesis 41

I.2.2. Objectives 41

II. Materials and methods 43

II.1. Subject selection 43

II.2. Data collection and follow-up 46

II.3. Definition of intrinsic subtypes of breast cancer 46

II.4. Literature search strategy and selection criteria 51

II.5. Genotyping and quality controls 53

II.6. Statistical analysis 58

II.6.1. Explanatory variables 58

II.6.2. Distribution of intrinsic subtypes 62

II.6.3. Heterogeneity in etiology of breast cancer by intrinsic subtypes 62

II.6.4. Heterogeneity in prognosis of breast cancer by intrinsic subtypes 64

III. Results 66

III.1. Distribution of intrinsic subtypes 66

III.1.1. Baseline characteristics 66

III.1.2. Distribution of intrinsic subtypes in study subjects 68

III.1.3. Distribution of intrinsic subtypes by meta-analysis 71

III.2. Heterogeneity in etiology of breast cancer by intrinsic subtypes 76

III.2.1. Baseline characteristics by intrinsic subtypes 76

III.2.2. Association of non-genetic factors on breast cancer risk by intrinsic subtypes 83

III.2.3. Association of genetic factors on breast cancer risk of intrinsic subtypes 95

III.3. Heterogeneity in prognosis of breast cancer by intrinsic subtypes 102

III.3.1. Association of intrinsic subtypes on breast cancer survival 102

III.3.2. Association of non-genetic factors on breast cancer survival by intrinsic subtypes 108

III.3.3. Association of known genetic factors on breast cancer survival by intrinsic subtypes 113

III.3.4. Genome-wide association study on breast cancer survival by intrinsic subtypes 120

IV. Discussions 126

IV.1. Distribution of intrinsic subtypes 126

IV.2. Heterogeneity in etiology of breast cancer by intrinsic subtypes 128

IV.2.1. Association of non-genetic factors on breast cancer risk by intrinsic subtypes 128

IV.2.2. Association of genetic factors on breast cancer risk by intrinsic subtypes 131

IV.3. Heterogeneity in prognosis of breast cancer by intrinsic subtypes 133

IV.3.1. Association of non-genetic factors on breast cancer survival by intrinsic subtypes 133

IV.3.2. Association of genetic factors on breast cancer survival by intrinsic subtypes 134

IV.4. Strength and limitation 136

IV.5. Translational relevance and impact 139

V. Summary and conclusion 142

VI. References 145

VII. Appendix 190

국문초록 215

List of Tables

Table I-1. Definition of intrinsic subtypes of breast cancer by literature review. 25

Table I-2. Previous studies on non-genetic risk factors of breast cancer by intrinsic subtypes 30

Table I-3. Previous studies on non-genetic risk factors of breast cancer by intrinsic subtypes 31

Table I-4. Previous genome-wide association studies on genetic risk factors of breast cancer. 32

Table I-5. Previous studies on genetic risk factors of breast cancer by intrinsic subtypes. 35

Table I-6. Previous studies on genetic and non-genetic prognostic factors of breast cancer by intrinsic subtypes. 39

Table I-7. Previous genome-wide association studies on genetic prognostic factors of breast cancer. 40

Table II-1. Definition of intrinsic subtypes of breast cancer in the current study. 50

Table II-2. Functional information on genetic factors included in the current study. 55

Table III-1. Baseline characteristics of breast cancer patients. 67

Table III-2. Distribution of intrinsic subtypes and stratified distribution by age groups and TNM stages. 69

Table III-3. Distribution of intrinsic subtypes by race through systematic review and meta-analysis. 72

Table III-4. Associations of non-genetic factors between intrinsic subtypes of breast cancer 81

Table III-5. Non-genetic factors between breast cancer patients and healthy controls. 87

Table III-6. Associations of non-genetic factors on breast cancer risk by intrinsic subtypes. 87

Table VII-7. Associations of non-genetic factors on breast cancer risk by intrinsic subtypes through meta-analysis by age groups. 93

Table III-8. Association of previously identified genetic risk factors on breast cancer risk by intrinsic subtypes. 97

Table III-9. Associations of clinico-pathological factors with recurrences or deaths in overall breast cancer. 103

Table III-10. Associations of non-genetic factors with recurrences or deaths of overall breast cancer. 106

Table III-11. Associations of non-genetic factors with recurrences breast cancer by intrinsic subtypes. 109

Table III-12. Associations of non-genetic factors with deaths of breast cancer by intrinsic subtypes. 111

Table III-13. Association of previously identified genetic risk factors with recurrences of breast cancer by intrinsic subtypes. 115

Table III-14. Association of previously identified genetic prognostic factors on recurrences of breast cancer by intrinsic subtypes. 118

Table III-15. Association of genetic factors on recurrences of breast cancer by intrinsic subtypes. 121

List of Appendix Tables

Appendix Table VII-1. Sensitivity analysis on distribution of intrinsic subtypes of breast cancer by race through meta-analysis. 190

Appendix Table VII-2. Association of body mass index between HR- HER2- and non-HR- HER2- tumors by case-case analysis. 191

Appendix Table VII-3. False discovery rate test on associations of non-genetic factors on breast cancer risk by intrinsic subtypes. 192

Appendix Table VII-4. Associations of non-genetic factors on risk of HR+ HER2- tumors by age groups. 194

Appendix Table VII-5. Associations of non-genetic factors on risk of HR+ HER2+ tumors by age groups. 196

Appendix Table VII-6. Associations of non-genetic factors on risk of HR- HER2+ tumors by age groups. 198

Appendix Table VII-7. Associations of non-genetic factors on risk of HR- HER2- tumors by age groups. 200

Appendix Table VII-8. False discovery rate test on association of previously identified genetic factors through genome-wide... 202

Appendix Table VII-9. False discovery rate test on associations of non-genetic factors on disease-free survival of breast cancer by... 205

Appendix Table VII-10. False discovery rate test on associations of non-genetic factors on overall survival of breast cancer by... 207

Appendix Table VII-11. Clinico-pathological characteristics of breast cancer patients by intrinsic subtypes and stages of genome-... 209

Appendix Table VII-12. False discovery rate test on association of previously identified genetic factors through genome-wide... 210

Appendix Table VII-13. Distribution of estrogen and progesterone receptor and human epidermal growth factor receptor 2 between... 213

List of Figures

Figure I-1. Hypothetical diagram of the current study on heterogeneity in etiology and prognosis of breast cancer by intrinsic... 42

Figure II-1. Selection of eligible study subjects in the current study. 45

Figure II-2. Estrogen and progesterone receptor testing by immunohistochemistry. 48

Figure II-3. Human epidermal growth factor receptor 2 testing by immunohistochemistry and fluorescence in situ hybridization. 49

Figure II-4. Process flows to select previous studies for meta-analysis on distribution... 52

Figure II-5. Selected genetic loci in the current study. 61

Figure III-1. Distribution of intrinsic subtypes and stratified distribution by age groups and TNM stages. 70

Figure III-2. Distribution of intrinsic subtypes by race through meta-analysis. 75

Figure III-3. Associations of premenopausal BMI on breast cancer risk by intrinsic subtypes. 90

Figure III-4. Associations of parity on breast cancer risk by intrinsic subtypes. 91

Figure III-5. Associations of more number of children on breast cancer risk by intrinsic subtypes. 92

Figure III-6. Associations of single-nucleotide polymorphism rs2046210 on breast cancer risk by intrinsic subtypes. 100

Figure III-7. Associations of single-nucleotide polymorhpisms rs10069690 and rs9485372 on breast cancer risk by intrinsic subtypes. 101

Figure III-8. Disease-free survival by intrinsic subtypes of breast cancer. 104

Figure III-9. Overall survival by intrinsic subtypes of breast cancer. 105

Figure III-10. Regional plots for association of single-nucleotide polymorphism... 122

Figure III-11. Regional plots for association of single-nucleotide polymorphism... 123

Figure III-12. Association of single-nucleotide polymorphism rs166870 and disease-... 124

Figure III-13. Association of single-nucleotide polymorphism rs10825036 and... 125

Figure V-1. Summary of non-genetic factors on the risk and prognosis of breast cancer by intrinsic subtypes. 143

Figure V-2. Summary of genetic factors on the risk and prognosis of breast cancer by intrinsic subtypes. 144

List of Appendix Figures

Appendix Figure VII-1. Sensitivity analysis on distribution of intrinsic subtypes of breast cancer by race through meta-analysis. 214

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