Retinoblastoma: a model of oncogenesis.

Early events in oncogenesis can be understood in retinoblastoma (RB) because of several unusual clinical features: intraocular location of the tumor results in early diagnosis and frequent cure by surgery; survivors demonstrate a dominantly transmitted hereditary predisposition to RB; heritable and nonheritable subgroups can usually be distinguished clinically. Mathematical analysis of the clinical data lead Knudson to formulate the hypothesis that two mutations are required for RB tumor production. The first mutation (M1) occurs in the germ line of hereditary RB patients and in a somatic retinal cell in nonhereditary RB patients; for all RB patients, the second mutation (M2) occurs in the somatic retinal cell that becomes malignant. The locus of M1 (the RB locus), suspected on the basis of deletion patients to be at 13q14, was confirmed by linkage to the esterase D (ESD) gene locus in hereditary families. Studies utilizing multiple polymorphic markers, (ESD isoenzymes, restriction fragment length polymorphisms and karyotypic heteromorphisms) have shown that a somatic change from heterozygosity in constitutional cells to homozygosity in RB tumors occurs frequently for chromosome 13q but not for other chromosomes. Thus, M2 produces malignancy by somatic loss of the normal allele on the homologous chromosome 13. The normal allele at the RB locus probably regulates differentiation. In its absence, uncontrolled proliferation occurs. The genetic mechanisms defined in RB for expression of a dominantly inherited mutation may well apply to other malignancies and other dominantly inherited diseases.