Page 251 - 20dynamics of cancer

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the enhanced rate of symmetric mitoses, and more rapid wound heal-
ing may be more carcinogenic. So a variant that increased the rate of
wound healing might rise to high frequency even though it shifts cancer
incidence to earlier ages.
In general, when a variant shifts cancer to earlier ages and occurs
at unexpectedly high frequency, pleiotropy is a reasonable hypothesis.
However, it is often difficult to figure out the multiple effects of a variant
and the respective consequences for survival and reproduction.

OVERDOMINANCE AND EPISTASIS: VARIABLE GENETIC BACKGROUND
Overdominance occurs when, at a locus with two alternative alleles,
the heterozygote is more fit than either homozygote. Sickle cell anemia
provides the classic example. An individual with one sickle cell vari-
ant allele enjoys protection against malaria, but an individual with two
copies of the variant suffers severe disease from aberrations in red blood
cells. Those opposing benefits and costs influence the frequency of the
sickle cell variant.
Overdominance probably occurs rarely for variants that directly cause
significant shifts of cancer to earlier ages. Most carcinogenic variants act
in a physiologically recessive way, such that a cell with one normal copy
and one variant copy has a normal phenotype. Deleterious effects at the
cellular level arise only when both allelic copies suffer loss of function.
However, an individual needs to carry only one mutated copy to be at
risk; the cancerous phenotype arises after somatic mutation knocks out
the second copy in a small fraction of cells. So, although most cancer-
predisposing mutations are physiologically recessive, they are inherited
as dominant alleles (Marsh and Zori 2002). So far, only three genes
(RET , MET , and CDK4) have been found with inherited variants that
act dominantly within cells (as oncogenes) among 31 cancer genes with
single locus predisposing variants (Marsh and Zori 2002).
Pleiotropic overdominance may occur, in which a heterozygote locus
that predisposes to cancer has beneficial effects on some other pheno-
type. Probably some cases of pleiotropic overdominance will eventually
be discovered, but no evidence presently suggests this process as a ma-
jor force maintaining genetic variability in predisposition.
Epistasis arises when the effect of a variant depends on the presence
or absence of variants at other loci. Epistasis is much like overdomi-
nance: both processes cause changes in the phenotypic consequences of