Page 208 - 20dynamics of cancer

CARCINOGENS 193

Table 9.1 Carcinogen-induced H-ras substitutions in mouse skin papillomas

Carcinogen ∗ Substitution (codon) Frequency in papillomas
MNNG G 35 → A (12) 11/15
MNU G 35 → A (12) 5/12
DMBA A 182 → T (61) 45/48
MCA G 182 → T (61) 4/20
MCA G 38 → T (13) 4/20
∗ Abbreviations: MNNG, N-methyl-N -nitro-N-nitrosoguanidine; MNU, meth-

ylnitrosourea; DMBA, 7,12-dimethylbenz[a]anthracene; MCA, 3-methylcholan-
threne. Initial carcinogen treatment followed by repeated application of TPA,
12-O-tetradecanoyl-13-acetylphorbol. Data from Brown et al. (1990).

the most frequent DNA base substitutions in response to four different
carcinogens, measured in papillomas that did not progress to carcino-
mas. In this case, the carcinogens were applied in one dose at the start
of treatment (an initiator), and most likely acted as direct mutagens.
The initial treatment with one of the mutagens listed in Table 9.1 was
followed by repeated application of a mitogen, TPA.
The observed substitution spectrum in response to an initial carcino-
gen probably results from two processes. First, the initial carcinogen
treatment causes a particular spectrum of genetic changes. That pri-
mary spectrum depends on the biochemical action of the carcinogen
with respect to DNA damage and repair. Second, among the variation
caused by those initial changes, only certain mutations become ampli-
fied to form papillomas. In this case, selection amplified those cells that
carry changes to the Ras protein and abrogation of negative regulation
of mitogenic signals.
I summarized results on H-ras mutation (Table 9.1) to emphasize that
different carcinogens often cause different spectra of heritable varia-
tion. Several other studies report carcinogen-specific spectra of herita-
ble change to DNA sequence, epigenetic marks, or karyotypic alterations
(reviewed by Lawley 1994; Turker 2003).
Mutation of H-ras appears to be a common early step of skin car-
cinogenesis in both mice and humans (Brown et al. 1995). Two alterna-
tive hypotheses could explain why H-ras mutations arise early in exper-
imental studies of chemical carcinogenesis in mice. First, the particular
carcinogens may produce a mutational spectrum that favors H-ras vari-
ation and selection. Second, amplification of H-ras mutation may be a