Page 209 - 20dynamics of cancer

194 CHAPTER 9

favored early step in skin carcinogenesis, so that early change in H-ras is
not strongly dependent on the particular spectrum of heritable change
caused by a direct mutagen.
How do chemical carcinogens affect different stages of progression?
The stage at which p53 mutations occur in skin carcinogenesis and the
spectrum of mutations to that gene provide some clues (Brown et al.
1995; Frame et al. 1998). Burns et al. (1991) observed no p53 mutations
in benign papillomas, an early stage in carcinogenesis, whereas they
found that 25% of later stage carcinomas had p53 mutations. It may be
that early p53 mutations are actually selected against in skin carcino-
genesis. In three different studies that applied an initial mutagen to
mouse skin, heterozygote p53 +/− mice had fewer papillomas than did
wild-type p53 +/+ mice (Kemp et al. 1993; Greenhalgh et al. 1996; Jiang
et al. 1999). Another study showed that p53 +/− mice had a three-fold
increase in progression of papillomas to carcinomas, demonstrating a
causal role of p53 mutation in later stages of carcinogenesis (Brown et al.
1995).
In three different chemical carcinogen treatments of mouse skin, the
particular spectrum of p53 mutations depended on the treatment. When
an initial mutagen, DMBA, was followed by the mitogen, TPA, most p53
changes were loss of function mutations, including frameshifts, dele-
tions, and the introduction of stop codons. Repeated application of
DMBA led to five carcinomas with one deletion and four transversion
mutations in p53. Repeated application of the mutagen MNNG led to
four carcinomas with G → A transitions in p53 (Brown et al. 1995).

HYPOTHESES AND TESTS
I describe a series of hypotheses and tests to show how one might
in principle connect particular mechanisms of carcinogen action to con-
sequences for multistage carcinogenesis. Some of the tests may not be
experimentally well posed or practical to do, but they should help to
stimulate thought about how to develop new, more practical tests that
provide information about mechanism.
Measuring a rate of transition directly is difficult, so I focus on the
number of transitions and the order of effects.

Hypothesis for number of steps affected by a carcinogen.—A treatment
affects only a subset of rate-limiting steps.