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80 CHAPTER 4

changes that influence progression. Other authors, interested in the
particular mechanisms of change that underlie progression, emphasize
the distinctions between different kinds of genomic changes.
An early distinction arose between point mutations to particular bases
and chromosomal instability, which causes a variety of broad karyotypic
changes that often affect dosage and gene expression. Some have argued
that mutations causing chromosomal instability likely arise early in pro-
gression in many tumors (Nowell 1976; Rajagopalan et al. 2003; Michor
et al. 2004). Such chromosomal instability could explain the accumula-
tion of numerous genetic changes in a cell lineage, ultimately leading to
malignant disease.
Recent evidence points to an important role for various epigenetic
changes in contributing to the overall rate of genomic changes in pro-
gression. Epigenetic changes include methylation and acetylation of hi-
stone proteins and methylation of DNA (Kuo and Allis 1998; Breivik
and Gaudernack 1999b; Wang et al. 2001; Jones and Baylin 2002; Eg-
ger et al. 2004; Feinberg and Tycko 2004; Fraga et al. 2005; Genereux
et al. 2005; Hu et al. 2005; Robertson 2005; Seligson et al. 2005; Sontag
et al. 2006). Both methylation and acetylation can strongly influence
gene expression, and both tend to be inherited through a cellular lin-
eage. Complex molecular regulatory systems control these epigenetic
processes, determining the rate of change and the stability of inherited
changes. The regulatory systems are often perturbed in tumors, causing
enhanced rates of epigenetic changes—a different mechanistic form of
the mutator phenotype.
With regard to kinetics, epigenetic changes simply provide another
contributing factor to the speed at which rate-limiting steps in progres-
sion may be passed. If one includes epigenetic change, it may not be
so hard to explain how cell lineages accumulate multiple hits over the
course of a lifetime. With regard to mechanism, some have proposed
that epigenetic change presents a new paradigm of progression (Prehn
2005), but my focus remains on kinetic issues.

4.9 Summary

This chapter completes the background on biological observations of
incidence and progression, and on the history of theories to explain pat-
terns of incidence. These background chapters discussed quantitative