Page 81 - 20dynamics of cancer

66 CHAPTER 4

(1964) stated: “Although for a specific cancer the inherited predisposi-
tion usually affects only a single autosomal locus ... the phenotypic ex-
pression in adults should generally involve somatic mutation of the gene
homologous with the inherited allele, together with somatic mutation of
homologous genes at another locus.” This combination of inherited and
somatic mutation explains why the “commonest form of predisposing
inheritance appears to be a simple Mendelian dominant of incomplete
penetrance.”
Anderson (1970) summarized further evidence of autosomal domi-
nant inheritance of cancer predisposition for certain types of tumors,
including retinoblastoma. In discussion of Anderson’s paper, DeMars
(1970) stated:

I think many pedigrees are consistent with the notion that one of
the parents in these families might be heterozygous for a reces-
sive and that the neoplasms appear as a result of subsequent so-
matic mutations in which individual cells become homozygous for
a recessive neoplasm-causing gene. Can you critically exclude that
possibility in any of the cases that you called autosomal dominant?
It’s obviously important if we want to understand the relationship
between the genotypes and the phenotype called cancer.

Ashley (1969a) made the first comparison of age-specific incidence
between inherited and noninherited forms of the same cancer. He com-
pared polyposis coli, an inherited form of colon cancer, with noninher-
ited cases. He concluded that “the slope of age dependence for the de-
velopment of colonic cancer is less steep in the case of individuals car-
rying the gene for polyposis coli than in the general population.” Ashley
argued that this comparison supported multistage theory, where transi-
tions between stages arise by genetic mutations (hits): “the difference in
slopes suggests that more ‘hits’ are required in the case of an individual
in the general population before a colonic cancer will develop than is
the case in an individual who has, in his genome, the gene [mutation]
for polyposis coli.”
Knudson (1971) compared age-onset patterns of retinoblastoma be-
tween inherited and noninherited forms. In his introduction, Knudson
placed his work in the context of multistage progression, in which pro-
gression is driven by genetic mutations: