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 G1 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.

Keywords: retinoblastoma; hereditary tumour predisposition; tumour suppressor gene; cancer genetics

Figure 1.

Organisation of the retinoblastoma (RB1) gene and protein, pRB, and location of some mutations associated with incomplete penetrance. (a) Genomic organisation of the RB1 gene. (b) Organisation of the 27 exons containing the open reading frame. (c) Structure of the pRb protein. A and B, A/B pocket domain; NLS, nuclear localisation signal; filled circles, phosphorylation sites. (d) Location of missense substitutions and in‐frame deletions known to be associated with incomplete penetrance and mild expressivity.

Figure 2.

Pedigrees with retinoblastoma. Filled symbols, bilateral retinoblastoma; half‐filled symbols, unilateral retinoblastoma; mt, heterozygous carriers; n, family members who have not inherited the mutant allele. (a) Family with complete penetrance associated with a frameshift mutation (651X). (b) Family with incomplete penetrance and mild expressivity associated with an exonic splice site mutation that results in skipping of exon 13. (c) A family segregating the recurrent mutation IVS6+1G>T. This and other families with this mutant allele show differential penetrance depending on the parental origin of the mutant allele (Klutz et al., ).



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Further Reading

DiCiommo D, Gallie BL and Bremner R (2000) Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. Seminars in Cancer Biology 10: 255–269.

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Lohmann DR (1999) RB1 gene mutations in retinoblastoma. Human Mutation 14: 283–238.

Lohmann DR, Gerick M, Brandt B et al. (1997) Constitutional RB1‐gene mutations in patients with isolated unilateral retinoblastoma. American Journal of Human Genetics 61: 282–294.

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Zheng L and Lee WH (2001) The retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Experimental Cell Research 264: 2–18.

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Lohmann, Dietmar R, and Gallie, Brenda L(Mar 2011) Retinoblastoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006053.pub2]