Mutant alleles of the RBI locus on human chromosome 13q 14 have previously been linked to the development of retinoblastoma, a tumor of embryonal neural retina. In the bilateral form of the disease, inheritance of a germinal mutation at this locus predisposes each retinal cell to a subsequent second somatic event which results in the formation of the retinoblastoma tumor. Spontaneous unilateral tumor occurrence appears to result from two sequential somatic events. Survivors of the bilateral form of this eye tumor are at substantially increased risk for subsequent development of second primary cancers, particularly osteosarcoma, a bone cancer. Conversely, survivors of unilateral retinoblastoma exhibit the same likelihood of development of osteosarcoma as the general population.

In order to determine whether osteosarcoma and retinoblastoma share a common pathogenetic mechanism, we determined restriction fragment length alleles at loci on chromosome 13 in DNA from constitutional tissues of bilaterally affected retinoblastoma patients as well as from their osteosarcoma tumors. These analyses indicated that the loss of constitutional heterozygosity in the tumors occurred specifically for chromosome 13 and appeared to involve the same chromosomal region as that previously identified in retinoblastoma tumors. Similarly, specific loss of constitutional chromosome 13 heterozygosity was also apparent in sporadic osteosarcomas. These results suggest that both diseases are due to the mitotic unmasking of pleitropic recessive mutant alleles at the RBI locus, and that the clinical occurrence of mixed cancer families such as these may be due to the differential expression of a single recessive mutation.