Page 215 - 20dynamics of cancer

200 CHAPTER 9

slow down less for repair or commit apoptosis less often than do MMR-
competent cells.
By contrast, distal colorectal tumors tend to have chromosomal insta-
bility caused by loss of the mechanisms that maintain genomic integrity,
such as the nucleotide excision repair (NER) pathway. Breivik and Gaud-
ernack (1999a) argue that the bulky-adduct-forming (BAF) carcinogens
may arise primarily from dietary and environmental factors and concen-
trate primarily in the distal colorectum.
The argument for distal tumors can be summarized as follows. BAF
carcinogens concentrate in the proximal colorectum. The NER pathway
primarily repairs the damage caused by BAF agents. Those cells that lose
the NER repair pathway gain an advantage in the selective environment
created by BAF agents, because NER-deficient cells slow down less for
repair or commit apoptosis less often than do NER-competent cells.
By this theory, a carcinogen may act in three stages. First, direct mu-
tagenesis creates variant cell lineages. Second, selection favors clonal
expansion of variant cells that lose repair function for the type of mu-
tagenic damage caused by the carcinogen. Third, direct mutagenesis of
cells that lack associated repair processes may speed the rate at which
subsequent transitions occur through the steps of multistage progres-
sion.

TEST
By test, I mean the ways in which to study the predicted consequences
of a carcinogen for age-specific incidence. This section focuses on car-
cinogens that may act both as direct mutagens and as selective agents.
No clear theory has been defined to formulate hypotheses for the rela-
tion between the dosage of such carcinogens and the patterns of age-
specific incidence.
I can speculate a bit. As mentioned above, a directly mutagenic agent
may have three separate effects: initial mutagenesis, secondary selective
expansion of mutator clones, and tertiary mutagenesis.
Consider a particular mutagen and an associated DNA repair system
that fixes the kind of damage caused by the mutagen. A knockout geno-
type with reduced or absent repair function should respond differently
to the carcinogen when compared to the wild type. In particular, the
incidence rate of the knockout should be insensitive to the initial muta-
genesis directed at the repair system under study, because that repair