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3 Moleculm' cloning and fUllction of tumol' suppl'essol' genes
In the last few years an enormous progress was seen in the cloning and/or identification of
genes involved in hereditary cancer syndromes and tumor progression. This section gives an
overview of some of these genes together with a short description of their putative function
and possible involvement in other tUlllor types.
3.1 The Retinoblastoma (RbI) gene
The RbI gene was isolated in 1986, on the basis of its primary role in retinoblastoma
development (Friend et a!., 1986; Fung et a!., 1987; Lee et a!., 1987). The gene
encompasses 200 kb on chromosome 13ql4 and encodes a 105 kD nuclear phosphoprotein.
Most alterations observed in the gene in retinoblastoma are deletions and nonsense mutations
and involve both alleles. These changes result in a truncated or absent protein and are in
agreement with the suspected loss of function mutations as was postulated for tumor
suppressor genes. Inactivating mutations of both copies of the gene occur in many other
tumor types including breast carcinoma, prostate carcinoma, osteosarcoma, soft tissue
sarcoma and small-cell lung carcinoma (Bookstein et al. I 1990a; Friend et al., 1987; Harbour
et a!., 1988; Hensel et a!., 1990; Lee el a!., 1988; T'Ang et a!., 1988; Varley et a!., 1989;
Yokota et a!., 1988). This indicates Ihat loss of Rb I function is important in the
tumorigenesis of many tumors. In hereditary retinoblastoma 5-10% of the patients also
develop osteosarcomas and soft tissue sarcomas. An explanation for the finding that they
have no increased risk for other tumors might be that for the other tumors mutations in other
genes must happen first. The growlh suppressing role of the wild-type (wt) Rb I protein was
clearly illuslrated by experiments in which the wt RbI gene was introduced into Rbi-deficient
tumor cells. These studies demonstrated suppression of cell-growth and tUlllorigenicity
(Huang et a!., 1988; Bookstein et a!., 1990b; Sumegi et a!., 1990; Takahashi et a!., 1991;
Goodrich et a!., 1992a).
Insight into the function of Rbi started with the finding that DNA tUlllor virus
encoded oncoproteins (EI A, large T antigen and E7) form complexes with the host cell Rb I
protein (DeCaprio el a!., 1988; Whyte et a!., 1988; Dyson et a!., 1989). The current idea
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