Prediction of the Risk of Hereditary Retinoblastoma, Using DNA Polymorphisms within the Retinoblastoma Gene

Abstract

Using molecular cloning, we earlier isolated the "retinoblastoma gene"; mutations or deletions at this locus are associated with the hereditary predisposition to some human cancers, especially retinoblastoma and osteosarcoma. To develop diagnostic tests for such a predisposition, we identified restriction-fragment-length polymorphisms (RFLPs) within the retinoblastoma gene and tested their usefulness in predicting the risk of cancer in 20 families with members who had hereditary retinoblastoma. We were able to make predictions in 19 of the 20 kindreds. In 18 kindreds, we demonstrated a consistent association of marker RFLPs with the mutation predisposing to retinoblastoma. In the 19th kindred, there may be a lack of cosegregation of the DNA polymorphisms within the gene and the site of the mutation predisposing to retinoblastoma. However, there is uncertainty about the clinical diagnosis of the retinal lesion in a key member of this kindred; if the lesion is not a retinoblastoma, there is no discrepancy between the DNA polymorphisms and the retinoblastoma trait. We conclude that it is feasible and clinically useful to use these DNA polymorphisms to determine the risk of cancer.

Loss of the retinoblastoma susceptibility gene (RB1) is a frequent and early event in prostatic tumorigenesis

“…This tissue showed retention of the 3' locus within intron 17 as revealed by probe p68RS2.0. Intron 17 is large and the XbaI and VNTR polymorphism are 20kb apart (Wiggs et al, 1988). Densitometry showed a greater than 60% reduction in the size of the deleted allele from the BPH tissue when compared with its counterpart derived from blood.…”

Recessive mechanisms of malignancy

“…RFLP analysis has already been used as an approach to ante-natal diagnosis in pedigrees at risk for retinoblastoma (Cavenee et al, 1986;Wiggs et al, 1988) …”

Follow-up of retinoblastoma patients having prenatal and perinatal predictions for mutant gene carrier status using intragenic polymorphic probes from the RB1 gene

“…Only 15% of patients have a positive family history although all bilateral cases (around 40%) are generally considered to be germ line carriers of a predisposing mutation (Knudson, 1971). The Rb phenotype segregates as an autosomal dominant trait with high penetrance (Vogel, 1979 (Wiggs et al, 1988). These probes form the basis of linkage studies in the analysis of Rb families worldwide and have been successfully applied in 80-90% of families (Wiggs et al, 1988;Scheffer et al, 1989;Onadim et al, 1990).…”