Mechanistic Hypotheses and Comparative Tests

First, cancer incidence rises more rapidly with duration of exposure than with dosage. In terms of lung cancer, incidence rises more rapidly with number of years of smoking than with number of cigarettes smoked per year. Second, lung cancer incidence remains approximately constant after cessation of smoking but rises in continuing smokers. Traditional explanations suggest that carcinogens affect only a subset of stages in progression. Such specificity in...

Theory I

To test hypotheses about how particular biochemical processes affect cancer, we need quantitative predictions for how biochemical changes alter the age of cancer onset. This chapter develops the quantitative theory of progression dynamics. The first section outlines my strategy for presentation. I divide each quantitative analysis into a pr cis that gives the main points, a mathematical presentation of the analytical details, and a set of conclusions. The second section solves the basic model...

Somatic Mosaicism

In each cell division, new heritable changes may arise in DNA sequence, in DNA methylation, and in modifications to histone proteins. A change in the first few post-zygotic divisions alters many descendants a change in an epithelial stem cell modifies the descendants within the local tissue compartment. In either case, the organism develops into a mosaic of different genotypes. Most observations of mosaicism derive from some spectacularly noticeable change. Pigmented skin patches mark the...

Mutations during Development

Renewing tissues typically have two distinct phases in the history of their cellular lineages. Early in life, cellular lineages expand exponentially to form the tissue. For the remainder of life, stem cells renew the tissue by dividing to form a nearly linear cellular history. Figure 13.1 shows a schematic diagram of the exponential and linear phases of cellular division. Mutations accumulate differently in the exponential and linear phases of cellular division (Frank and Nowak 2003). During...

Discrete Genetic Heterogeneity

Some individuals may inherit mutations that cause them at birth to be one or more steps along the pathway of progression. in this section, I analyze incidence and acceleration when individuals separate into discrete genotypic classes. After deriving the basic mathematical results, i illustrate how genetic heterogeneity affects epidemiological pattern. in the first case, one cannot distinguish between mutant and normal genotypes. if mutated genotypes are rare, then the aggregate pattern of...

Aims

The age-specific incidence curve reflects the processes that drive disease progression, the inheritance of predisposing genetic variants, and the consequences of carcinogenic exposures. It is easy to see that these various factors must affect incidence. But it is not so obvious how these factors alter measurable, quantitative properties of age-specific incidence. My first aim is to explore, in theory, how particular processes cause quantitative shifts in age-specific incidence. That theory...

A

Figure 14.4 Reconstruction of cell lineage histories from samples of adenoma and cancer tissues in two patients. The accumulation of microsatellite variation caused by mismatch repair deficiency (MMR-) measures time in proportion to the number of cell generations. The lengths of the branches represent inferred time. The dashed lines show the estimated 95 confidence intervals for the timing of the branch points. (a) Samples from an adenoma and an adjacent cancerous outgrowth. The branch between...

Multistage Progression in Colorectal Cancer

Colorectal cancer provides a good model for the study of morphological and genetic stages in cancer progression (Kinzler and Vogelstein 2002). Various precancerous morphologies can be identified, allowing tissue samples to be collected and analyzed genetically. Figure 3.1 shows the morphology of normal colon tissue. The epithelium has about 107 invaginations, called crypts. Cells migrate upward to the epithelial surface from the dividing stem cells and multiplying daughter cells at Figure 3.2...

Time Varying Transition Rates

The previous models assumed that transition rates between stages remain constant over time. Many process may alter transitions rates with age. In this section, I analyze two factors that may increase the transition rate between particular stages. In the first model, advancing age may be associated with an increase in transition rates between stages, for example, by an increase in somatic mutation rates Frank 2004a . In the second model, a cell arriving in a particular stage may initiate a clone...

Age

Figure 2.8 Fatal lung cancer in males for groups that quit smoking at different ages. The six curves defined in the legend show individuals who never smoked quit at age 0 , individuals who quit at ages 30, 40, 50, and 60, and individuals who never quit shown as age 99 . a Age-specific mortality per 100,000 population on a log scale versus age scaled logarithmically. Data extracted from Figure 2 of Cairns 2002 , originally based on the analysis in Peto et al. 2000 . Most cases of lung cancer are...