One hundred years of retinoblastoma Research: From the clinic to the gene and back again

Retinoblastoma (RB) has provided the prototype for the study of hereditary predisposition to cancer. An intraocular tumour of young children, it has both hereditary and sporadic forms. The familial form of RB is inherited as an autosomal dominant with high penetrance. In a small group of patients the identification of a constitutional deletion on the long arm of chromosome 13 indicated the location of the critical gene in region 13q14. Close linkage between the hereditary, non-deletion form of RB and the esterase-D gene, which is also located in 13q14, demonstrated that all hereditary forms of RB are due to defects in a gene at this locus. Analysis of the development of homozygosity for region 13q14 in sporadic tumours subsequently confirmed that probably all RB tumours are due to mutations in a single gene, RB1. Using molecular biological techniques a candidate gene has been isolated which maps to region 13q14 and which shows structural re-arrangements within tumour cells. Predisposing, hereditary mutations have also been shown to involve this gene thereby providing strong evidence for its authenticity. The isolation of DNA sequences from within this gene, which identify restriction fragment length polymorphisms, means that it is now possible to use them to carry out pre-natal diagnosis and identify individuals at high risk to tumour development.