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transformation came from somatic cell fusion experiments, which showed that fusion of
tumor cells with normal cells almost always results in the outgrowth of non tumorigenic
hybrids (Sager, 1985; Rarris, 1988). Sometimes these hybrid cells reverted back to a
tumorigenic state, which could be correlated with the loss of specific 'normal' chromosomes
(Stanbridge, 1990). These and other fusion experiments suggest that normal cells contain
genetic information capable of suppressing the neoplastic growth in the tumor cells. The
tumor cells have lost this information during their evolution from normal to tumor cells.
The second indication came from the existence of familial cancer. In 1971, Knudson
proposed the two-hit model for the development of retinoblastoma and one year later also for
Wilms' tumor (Knudson and Strong, 1972). This model was based on epidemiological
analyses of age of onset of multi focal (hereditary) versus single (sporadic) cases. It implies
that in heritable retinoblastoma the first hit is already present in the germline and only one
somatic hit is required for tumor formation. In sporadic cases two somatic mutational events
are needed, which explains the later age of onset in these patients. In 1973 Comings
suggested that the mutations were in the two alleles of the same gene. Definite proof for the
involvement of a recessive tumor suppressor gene was obtained when the nature of these
germline and somatic mutations became clear. First indications came from karyotypic
analyses of retinoblastoma tumor cells, which sometimes uncovered interstitial deletions that
involved chromosomal band 13ql4 (Yunis and Ramsay, 1978). Genetic analysis of blood and
tumor DNA pairs and the isolation of the retinoblastoma gene (Rbl) eventually confirmed
Knudson's theory (Cavenee et aI., 1983; Friend et aI., 1986; Fung et aI., 1987; Lee et aI.,
1987). These studies support the idea that a recessive tumor suppressor gene can contribute
to the development of a tumor when both alleles have been inactivated (Fig. I). The study
of other familial cancers have contributed towards the elucidation of more cancer
susceptibility loci and genes. The isolated genes responsible for the small fraction of
hereditary cancers are very useful for the study of these and the commoner sporadic cancers.
Although the predisposing Cancer genes are phenotypically dominant, at the genetic level they
are recessive (both copies of the gene should be inactivated). The apparent dominant
inheritance of these diseases reflects the high probability that the second allele is hit in a
somatic cell.
The third clue came from consistent and specific chromosome deletions in tumor
cells. Karyotyping and 'loss of heterozygosity' (LOR) studies clearly showed loss of
IS