Retinoblastoma

Abstract Retinoblastoma is a malignant tumour that originates in the developing retina and is usually diagnosed in children under age of 5 years. Mutations in both alleles of the tumour suppressor gene RB1 are a prerequisite for this tumour. In nonheritable retinoblastoma the two mutations have occurred in somatic cells and are not passed to offspring. Germline mutations in one allele of the RB1 gene cause heritable predisposition to retinoblastoma and a spectrum of other tumours (second cancers). In families this trait is autosomal dominant with variable phenotypic expression. Analysis of genotype–phenotype associations has shown that the mean number of tumour foci that develop in carriers of mutant RB1 alleles becomes smaller depending on which, and to what extent, functions of the normal allele are retained. The function of the RB1 gene product, pRb, that is understood best is as a gatekeeper that negatively regulates progression through G 1 phase of the cell cycle. However, a more important role in cancer progression may be prevention of deoxyribonucleic acid (DNA) instability. Recently, the RB1 gene was found to be imprinted, which may explain some of the observed parent‐of‐origin effects. Key Concepts: Two‐step mutational inactivation of the retinoblastoma gene ( RB1 ) is a prerequisite for development of retinoblastoma. Germline mutations in the RB1 gene cause heritable retinoblastoma which is transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. Variable phenotypic expression of heritable retinoblastoma is in part explained by allelic heterogeneity of RB1 gene mutations. In patients with nonheritable retinoblastoma, the two alleles of the retinoblastoma gene are inactivated by somatic mutations. The human RB1 gene is imprinted with skewed expression in favour of the maternal allele.