1. Introduction ................................................ 1
1.1. Aims .................................................. 2
1.2. How to Read ........................................... 4
1.3. Chapter Summaries ..................................... 5
PART I: BACKGROUND
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
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
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
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
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
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
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
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
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
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
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
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
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
15. Conclusions ............................................... 309
Appendix: Incidence ....................................... 314
References ................................................ 335
Author Index .............................................. 361
Subject Index ............................................. 373
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