ABSTRACT
Retinoblastoma is a childhood tumor of the eye, and is the classic example of a cancer caused by loss of a tumor suppressor gene. Retinoblastoma takes two forms: familial (40% of cases), which exhibits the inheritance pattern for a recessive gene and which frequently involves both eyes; and sporadic, which does not run in families and usually only occurs in one eye. It was suggested that retinoblastoma results from two mutations which inactivate both alleles of a single gene. In the familial form of the disease, one mutated allele is inherited in the germ line. On its own this is harmless, but the occurrence of a mutation in the remaining normal allele, in a retinoblast cell, causes a tumor. Since there are 107 retinoblasts per eye, all at risk, the chances of a tumor must be relatively high. In the sporadic, noninherited form of the disease, both inactivating mutations have to occur in the same cell, so the likelihood is very much less and only one eye is usually affected (Fig. 2). It should be noted that whilst familial retinoblastoma constitutes the minority of cases, it is responsible for the majority of tumors. The ‘two-hit’ hypothesis for retinoblastoma was also supported by evidence for loss of heterozygosity. The retinoblastoma gene (RB1) was provisionally located on human chromosome 13, by analysis of the genetics of families with the familial disease. By using hybridization probes for sequences closely linked to RB1, it was possible to show that the retinoblastoma cells of patients who were heterozygous for the linked sequences had only a single copy of the sequence, that is there had been a deletion in the region of the supposed RB1 gene in tumor cells, but not in nontumor cells.
