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CARCINOGENS 199

carcinogens that change the competitive hierarchy between genetically
or epigenetically variable cell lineages.
Consider, for example, an agent that kills cells by inducing apopto-
sis. That agent favors variant cell lineages that resist the induction of
apoptosis. Clonal expansion of the anti-apoptotic lineages follows. Anti-
apoptosis may often be an early step in carcinogenesis.
Variant cell lineages arise continuously. However, in the absence of
a selective agent to expand clones of predisposed cells, variant cell lin-
eages may have relatively little chance of completing progression. In
this regard, selective agents may play a key role in raising cancer inci-
dence. As always, variation and selection must complement each other
in the evolutionary process of transformation.

HYPOTHESIS

A recent theory proposes that carcinogens may act as both mutagens
and selective agents (Breivik and Gaudernack 1999b; Fishel 2001). In
the presence of a mutagen that causes a certain type of DNA damage,
selection may favor cells that lose the associated repair pathway. Cells
that lack the appropriate repair response may not stop the cell cycle to
wait for repair or may not commit apoptosis, whereas repair-competent
cells often slow or stop their cycle during repair. Thus, repair-deficient
cells could outcompete repair-competent cells, as long as the gain in
survival or in the speed of the cell cycle offsets any loss in division
efficacy caused by the increased accumulation of mutations.
In support of their theory, Breivik and Gaudernack (1999a) noted
the association between the physical location of colorectal tumors and
the loss of particular types of DNA repair. Proximal colorectal tumors
tend to have microsatellite instability caused by loss of mismatch repair
(MMR) genes. The MMR pathway repairs damage caused by methylating
carcinogens. Breivik and Gaudernack (1999a) argue that methylating
carcinogens often arise from bile acid conjugates that occur mainly in
the proximal colorectum.
The argument for proximal tumors can be summarized as follows.
Methylating carcinogens concentrate in the proximal colorectum. The
MMR pathway repairs the damage caused by methylating agents. Those
cells that lose the MMR repair pathway gain an advantage in the selective
environment created by methylating agents, because MMR-deficient cells