Retinoblastoma (Rb) is an embryonal tumor of early childhood occuring at a frequency of 1/23,000 live births. Approximately 40% of Rbs are due to a germinal mutation expressed as a dominant trait. This mutation also predisposes to the development of second nonocular malignancies notably sarcomas. It is unclear if all Rb patients have the same risk of developing second malignancies. Rb has served as a prototype for a model of tumorigenesis proposed by Knudsen. This model requires two successive event is germinal, while the second event may be chromosomal loss/duplication, deletion, point mutation or mitotic recombination resulting in functional loss of the normal allele. The recent observation tumor, and rhabdomyosarcoma, however, suggests that a phenomenon called genomic imprinting, may be involved in preferential inactivation of the paternal genome in these tumors. Genomic imprinting is an epigenetic process in which the expressivity/penetrance of a gene may be dependent upon the parental origin. We propose to study the role of imprinting, if any, in the development of second malignancies in hereditary Rb by, (1) determining if there are tissue specific differences in methylation of promotor in peripheral blood lymphocyte, retinoblastoma, and osteogenic sarcoma DNA samples, (2) analyze constitutional and tumor (1o and 2o) tissues for loss of heterozygosity, Rb gene deletions, Rb mRNA expression, and parental origin. (3) analyze our pedigrees (where possible) for parental origin of Rb gene in cases of nonocular malignancies.
