Dynamics of Cancer:
Incidence, Inheritance, and Evolution
Steven A. Frank

TABLE OF CONTENTS:

Chapter 1: Introduction 1
1.1 Aims 2
1.2 How to Read 4
1.3 Chapter Summaries 5

PART I: BACKGROUND

Chapter 2: Age of Cancer Incidence 17
2.1 Incidence and Acceleration 19
2.2 Different Cancers 20
2.3 Childhood Cancers 23
2.4 Inheritance 25
2.5 Carcinogens 29
2.6 Sex Differences 32
2.7 Summary 35

Chapter 3: Multistage Progression 36
3.1 Terminology 37
3.2 What Is Multistage Progression? 38
3.3 Multistage Progression in Colorectal Cancer 39
3.4 Alternative Pathways to Colorectal Cancer 43
3.5 Changes during Progression 49
3.6 What Physical Changes Drive Progression? 50
3.7 What Processes Change during Progression? 51
3.8 How Do Changes Accumulate in Cell Lineages? 55
3.9 Summary 58

Chapter 4: History of Theories 59
4.1 Origins of Multistage Theory 61
4.2 A Way to Test Multistage Models 65
4.3 Cancer Is a Genetic Disease 69
4.4 Can Normal Somatic Mutation Rates Explain Multistage Progression? 71
4.5 Clonal Expansion of
Premalignant Stages 74
4.6 The Geometry of Cell Lineages 76
4.7 Hypermutation, Chromosomal Instability, and Selection 78
4.8 Epigenetics: Methylation and Acetylation 79
4.9 Summary 80

PART II: DYNAMICS

Chapter 5: Progression Dynamics 85
5.1 Background 86
5.2 Observations to Be Explained 89
5.3 Progression Dynamics through Multiple Stages 90
5.4 Why Study Quantitative Theories? 93
5.5 The Basic Model 93
5.6 Technical Definitions of Incidence and Acceleration 94
5.7 Summary 95

Chapter 6: Theory I 96
6.1 Approach 97
6.2 Solution with Equal Transition Rates 97
6.3 Parallel Evolution within Each Individual 100
6.4 Unequal Transition Rates 103
6.5 Time-Varying Transition Rates 109
6.6 Summary 114

Chapter 7: Theory II 115
7.1 Multiple Pathways of Progression 116
7.2 Discrete Genetic Heterogeneity 120
7.3 Continuous Genetic and Environmental Heterogeneity 129
7.4 Weibull and Gompertz Models 136
7.5 Weibull Analysis of Carcinogen Dose-Response Curves 139
7.6 Summary 142

Chapter 8: Genetics of Progression 143
8.1 Comparison between Genotypes in Human Populations 144
8.2 Comparison between Genotypes in Laboratory Populations 154
8.3 Polygenic Heterogeneity 160
8.4 Summary 164

Chapter 9: Carcinogens 165
9.1 Carcinogen Dose-Response 166
9.2 Cessation of Carcinogen Exposure 180
9.3 Mechanistic Hypotheses and Comparative Tests 190
9.4 Summary 201

Chapter 10: Aging 202
10.1 Leading Causes of Death 203
10.2 Multistage Hypotheses 206
10.3 Reliability Models 207
10.4 Conclusions 209
10.5 Summary 209

PART III: EVOLUTION

Chapter 11: Inheritance 213
11.1 Genetic Variants Affect Progression and Incidence 214
11.2 Progression and Incidence Affect Genetic Variation 234
11.3 Few Common or Many Rare Variants? 243
11.4 Summary 250

Chapter 12: Stem Cells: Tissue Renewal 251
12.1 Background 252
12.2 Stem-Transit Program of Renewal 253
12.3 Symmetric versus Asymmetric Stem Cell Divisions 264
12.4 Asymmetric Mitoses and the Stem Line Mutation Rate 265
12.5 Tissue Compartments and Repression of Competition 269
12.6 Summary 270

Chapter 13: Stem Cells: Population Genetics 271
13.1 Mutations during Development 272
13.2 Stem-Transit Design 280
13.3 Symmetric versus Asymmetric Mitoses 283
13.4 Summary 285

Chapter 14: Cell Lineage History 286
14.1 Reconstructing Cellular Phylogeny 287
14.2 Demography of Progression 295
14.3 Somatic Mosaicism 304
14.4 Summary 308

Chapter 15: Conclusions 309

Appendix: Incidence 314
References 335
Author Index 361
Subject Index 373