Page 82 - 20dynamics of cancer

HISTORY OF THEORIES 67

The origin of cancer by a process that involves more than one dis-
creet [sic] stage is supported by experimental, clinical, and epidemi-
ological observations. These stages are, in turn, attributed by many
investigators to somatic mutations ... What is lacking, however, is
direct evidence that cancer can ever arise in as few as two steps and
that each step can occur at a rate that is compatible with accepted
values for mutation rates. Data are presented herein in support
of the hypothesis that at least one cancer (the retinoblastoma ob-
served in children) is caused by two mutational events.
Knudson concluded from his retinoblastoma data that individuals
who inherit one mutation follow the age-onset pattern expected if one
additional hit leads to cancer, whereas individuals without an inherited
mutation follow the kinetics expected if two hits leads to cancer. Knud-
son fit his data to particular one-hit and two-hit mathematical models.
However, his theoretical arguments in this paper ignored the way the
retina actually develops. In a later pair of papers, Knudson and his
colleagues produced a theory of incidence that accounts for retinal de-
velopment (Knudson et al. 1975; Hethcote and Knudson 1978).
The later papers had several parameters concerning retinal develop-
ment and mutation that the authors fit to the data. However, Knudson’s
great insight was simply that age-specific incidence of inherited and non-
inherited retinoblastoma should differ in a characteristic way if cancer
arises by two hits to the same cell. He obtained the data and showed
that very simple differences in incidence do occur.
In my view, nothing is more powerful than figuring out how to test
an important hypothesis by a simple comparison (Frank 2005; Frank
et al. 2005). Although Ashley (1969a) made essentially the same com-
parison of age-specific incidence between inherited and noninherited
forms of colon cancer, Knudson’s (1971) work achieved the status of a
classic whereas Ashley’s (1969a) paper is rarely cited. Ashley certainly
deserves credit for his accomplishment, but Knudson’s paper deserves
to be regarded among the few major achievements in this subject.
In retrospect, we can now see that Knudson’s paper made two major
contributions. First, he compared age-specific incidence curves between
inherited and noninherited cases. The inherited cases had increased
incidence by an amount consistent with an advance of progression by
one rate-limiting step. This approach provided a method of analysis by
which one could use quantitative comparison of age-specific incidence