Cancer Is a Genetic Disease

The role of somatic mutations in cancer was debated for many years. Witkowski (1990) puts that historical debate in context with a comprehensive time line of developments in cancer research interleaved with developments in basic genetics and molecular biology (see also Knudson 2001). Here, I mention a few of the highlights that provide background for evaluating theories of progression and incidence. Boveri (1914, 1929) often gets credit for the first comprehensive theory of somatic genetic...

Age of Cancer Incidence

Perturbations of the genetic and environmental causes of cancer shift the age-specific curves of cancer incidence. We understand cancer to the extent that we can explain those shifts in incidence curves. In this chapter, I describe the observed age-specific incidence patterns. The following chapters discuss what we can learn about process from these patterns of cancer incidence. The first section introduces the main quantitative measures of cancer incidence at different ages. The standard...

Progression and Incidence Affect Genetic Variation

The previous section described how genetic variants affect progression and incidence the pathway from genes through development to phenotype. In this section, I analyze how progression and incidence affect the frequency of variants in populations the pathway from phe-notype through natural selection to gene frequency. Many forces potentially influence gene frequency. The wide range of alternatives makes it easy to fit some model to the observed distribution of frequencies, but hard to determine...

Weibull Analysis of Carcinogen Dose Response Curves

Peto et al. (1991) provided the most comprehensive experiment and analysis of carcinogen dose-response curves. In their analysis, they compared the observed age-specific incidence of cancer (the response) over varying dosage levels. They described the incidence curves by fitting the data to the Weibull distribution. They also related the Weibull incidence pattern to the classic Druckrey formula for carcinogen dose-response relations. The Druckrey formula summarizes the many carcinogen...

Hypermutation Chromosomal Instability and Selection

Two process may accelerate the accumulation of genomic change. First, changes early in progression may accelerate the production of subsequent changes. Second, competition and selection between cell lineages that harbor various genomic changes would favor clonal expansion of more aggressive lines. Acceleration of Variation by Mutators Burdette (1955, p. 218) nicely summarized the potential role of mutators in early stages of progression A logical corollary to the somatic mutation hypothesis is...

Sex Differences in Incidence

Figures A.13-A.18 show the male female ratios for the major adult cancers. The plots highlight two kinds of information. First, the values on the y axis measure the male female ratio, with positive values for male excess and negative values for female excess. The scaling is explained in the legend of Figure A.13. Second, the trend in each plot shows the relative acceleration of male and female incidence with age. For example, in Figure A.13, the positive trend for lung cancer shows that male...

What Is Multistage Progression

Some people aim for the ordered list of necessary changes to cellular genomes and to tissues that cause aggressive cancers. Others emphasize the controversial hypothesis that two processes occur initiation by somatic mutation as a first stage, and promotion by mitotic stimulation as a second stage. There is no single correct way to pose the question. The listing of specific changes sets a useful although perhaps rather difficult goal. The testing of the...

Why Study Quantitative Theories

An ordered, linear sequence leaves out many of the complexities of carcinogenesis. However, it pays to begin with this simple model, to understand all of its logical consequences, and to study how well that model can predict changes in incidence. Following on the simple model, we can begin to explore alternatives, such as parallel lines of progression in different cellular lineages or incidence aggregated over different pathways. After I have analyzed the basic model, I will explore a range of...

Carcinogen Dose Response

Lung cancer incidence increases with roughly the fourth or fifth power of the number of years (duration) of cigarette smoking but with only the first or second power of the number of cigarettes smoked per day (dosage). The stronger response to duration than dosage occurs in nearly all studies of carcinogens. Peto (1977) concluded The fact that the exponent of dose rate is so much lower than the exponent of time is one of the most important observations about the induction of carcinomas, and...

Cessation of Carcinogen Exposure

Lung cancer incidence of continuing smokers increases with approximately the fourth or fifth power of the duration of smoking (Doll and Peto 1978). By contrast, incidence among those who quit remains relatively flat after the age of cessation (Doll 1971 Peto 1977 Halpern et al. 1993). In 1977, Richard Peto (1977) stated that the approximately constant incidence rate after smoking ceases is one of the strongest, and hence most useful, observational restrictions on the formulation of multistage...

Origins of Multistage Theory

Two different lines of thought developed the idea that cancer progresses through multiple stages. The first line arose from the observation that, in experimental animal studies, cancer often followed after sequential application of different chemical carcinogens. The second line arose from observations on the age-onset patterns of cancer, in which incidence often accelerates with age in a manner that suggests multiple stages in progression. In the 1920s, several laboratories began to apply...

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...

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...

The Geometry of Cell Lineages

Two aspects of cellular reproduction influence mutation accumulation. First, the rate of cell division influences the number of mutational events per unit time, because mutations arise primarily during cell replication. Second, the shape of cellular lineages determines how a single mutational event passes to descendant cells of a lineage. The rate at which a second hit strikes a descendant cell depends on how many of those descendant cells exist. Some tissues have extensive cell division early...

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...