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1 Cancer is a genetic disease
It is nowadays generally accepted that cancer can be considered as a genetic disease.
However, there are two clear differences between cancer and most other genetic diseases.
First, most cancers are caused essentially by somatic mutations, whereas all other genetic
diseases are caused solely by germline mutations. Second, for most cancer types at least two
mutations are required before a tumor may arise. For most pediatric and some adult tumors
only a limited number of mutations are supposed to be sufficient for tumor development
(Knudson, 1971, 1986; Haber and Housman, 1992). In contrast, most adult cancers appear
to require more than two genetic changes. This 'multiple-hit' concept of tumorigenesis stems
from several lines of evidence. First, most adult cancers show an exponential increase in
incidence with age, suggesting that the accumulation of different hits is involved in tumor
development (Vogelstein and Kinzler, 1993). Second, a dramatically increased incidence of
cancer has been observed in individuals with chromosome instability syndromes such as
Bloom's syndrome (Vijayalaxmi et aI., 1983; Seshadri et aI., 1987). Third, repeated
administration of mutagen to test animals is generally required before a tumor arises (Saffhill
et aI., 1985). Fourth, increasing evidence becomes available for the involvement of multiple
genetic alterations in common human tumors. The most extensively studied example is the
accumulation of genetic alterations observed in human colon tumors, in which mutations in
APe and ras found in adenomatous polyps have been classified as early events and mutations
in p53 and Dee as later events that may contribute to tumor progression (Fearon and
Vogelstein, 1990; section 3.3). In a specific human cancer, mutations in one particular gene
appear to precede those in others (Vogelstein and Kinzler, 1993), although after this first hit
the accumulation of changes rather than their specific order seems to be important for tumor
progression (Marx, 1989).
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