http://repub.eur.nl/res/aut/29299/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/23870/ 1994-11-02T00:00:00Z 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).