Molecular studies of loss of heterozygosity in retinoblastoma

Retinoblastoma (Rb) is a paediatric intraocular tumour in which predisposition can be inherited. Cases of Rb tumours can be divided into three types: familial cases, sporadic bilateral cases and sporadic unilateral cases. Familial and sporadic bilateral cases are usually categorised as hereditary while sporadic unilateral cases as non-hereditary. In both familial and non-familial forms of Rb, loss of heterozygosity of the Rb locus has been reported although its frequency in tumours has not so far been accurately determined. The cloning of the gene responsible for retinoblastoma (Rb1) has facilitated DNA studies and genetic counselling of patients. We have examined forty-five cases of retinoblastoma at five intragenic sites of the Rb1 locus, namely intron 1/BamH1, intron 17/Xba1, intron 24/TthIII1, intron 25/Dra1 and Rb1.20 VNTR. Thirty-six out of the forty-five cases (80%) were informative for these markers. Comparison of results between genomic DNA from peripheral blood and from tumours revealed that loss of heterozygosity of alleles could be detected in 50% of cases studied in which tumour samples were available. Investigation of parental origin of retained alleles showed that in all these cases, the paternal alleles were preferentially retained. The analysis of the genetic origin of mutations predisposing to retinoblastoma can facilitate new approaches for identifying recessive mutant genes that lead to cancer as well as to provide a conceptual basis for accurate prenatal predictions of cancer predisposition.