Genetics of the Pathophysiology of Retinoblastoma


Retinoblastoma is a malignant tumour that originates from cone precursors of the developing retina and is usually diagnosed in children under age of 5 years. This tumour emerges from cells with inactivating alterations of both alleles of the tumour suppressor gene RB1. In nonheritable retinoblastoma, these two alterations have occurred in somatic cells and are not passed to offspring. Variant alleles of the RB1 gene transmitted via the germline cause heritable predisposition to retinoblastoma and some other neoplasms (second cancers). In families, this trait shows autosomal dominant inheritance with variable phenotypic expression and incomplete penetrance. Analysis of genotype–phenotype associations has shown that the mean number of tumour foci that develop in carriers of mutant RB1 alleles varies depending on which, and to what extent the mutant allele has retained functions of the normal allele. The RB1 gene product, pRb, has a role in several cellular processes. One of its functions is to be a gatekeeper that negatively regulates progression through G1 phase of the cell cycle. The RB1 gene is imprinted and this may explain some of the observed parent‐of‐origin effects.

Key Concepts

  • Two‐step inactivation of the retinoblastoma gene (RB1) is a prerequisite for the development of retinoblastoma.
  • Germ‐line variants in the RB1 gene can cause heritable retinoblastoma that 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 variants.
  • 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; genomic imprinting

Figure 1. 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. Reproduced with permission from Klutz et al. . © The American Society of Human Genetics.


Acquaviva A, Ciccolallo L, Rondelli R, et al. (2006) Mortality from second tumour among long‐term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry. Oncogene 25: 5350–5357.

Albrecht P, Ansperger‐Rescher B, Schüler A, et al. (2005) Spectrum of gross deletions and insertions in the RB1 gene in patients with retinoblastoma and association with phenotypic expression. Human Mutation 26: 437–445.

Broaddus E, Topham A and Singh AD (2009) Incidence of retinoblastoma in the USA: 1975–2004. British Journal of Ophthalmology 93: 21–23.

Castera L, Sabbagh A, Dehainault C, et al. (2010) MDM2 as a modifier gene in retinoblastoma. Journal of National Cancer Institute 2010 (102): 1805–1808.

Chaussade A, Millot G, Wells C, et al. (2018) Correlation between RB1 germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy. European Journal of Medical Genetics. DOI: 10.1016/j.ejmg.2018.07.017.

Corson TW and Gallie BL (2007) One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes, Chromosomes and Cancer 46: 617–634.

Dimaras H, Khetan V, Halliday W, et al. (2008) Loss of RB1 induces non‐proliferative retinoma; increasing genomic instability correlates with progression to retinoblastoma. Human Molecular Genetics 17: 1363–1372.

Eloy P, Dehainault C, Sefta M, et al. (2016) A parent‐of‐origin effect impacts the phenotype in low penetrance retinoblastoma families segregating the c.1981C>T/p.Arg661Trp mutation of RB1. PLoS Genetics 12 (2): e1005888.

Gallie BL, Ellsworth RM, Abramson DH and Phillips RA (1982) Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? British Journal of Cancer 45: 513–521.

Gröbner SN, Worst BC, Weischenfeldt J, et al. (2018) The landscape of genomic alterations across childhood cancers. Nature 555 (7696): 321–327.

Kanber D, Berulava T, Ammerpohl O, et al. (2009) The human retinoblastoma gene is imprinted. PLoS Genetics 5: e1000790.

Kleinerman RA, Tucker MA, Tarone RE, et al. (2005) Risk of new cancers after radiotherapy in long‐term survivors of retinoblastoma: an extended follow‐up. Journal of Clinical Oncology 23: 2272–2279.

Kleinerman RA, Tucker MA, Abramson DH, et al. (2007) Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. Journal of the National Cancer Institute 99: 24–31.

Klutz M, Brockmann D and Lohmann DR (2002) A parent‐of‐origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene. American Journal of Human Genetics 71: 174–179.

Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 68: 820–823.

Lohmann DR and Gallie BL (2004) Retinoblastoma: revisiting the model prototype of inherited cancer. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 129: 23–28.

Ly P and Cleveland DW (2017) Rebuilding chromosomes after catastrophe: emerging mechanisms of chromothripsis. Trends in Cell Biology 27 (12): 917–930.

Macklin MT (1960) A study of retinoblastoma in Ohio. American Journal of Human Genetics 12: 1–43.

Mallipatna A, Gallie BL, Chévez‐Barrios P, et al. (2017) Retinoblastoma. In: Amin MB, Edge SB and Greene FL (eds) AJCC Cancer Staging Manual, 8th edn, pp. 819–831. New York, NY: Springer.

Marchong MN, Yurkowski C, Ma C, et al. (2010) Cdh11 acts as a tumor suppressor in a murine retinoblastoma model by facilitating tumor cell death. PLoS Genetics 6: e1000923.

McEvoy J, Nagahawatte P, Finkelstein D, et al. (2014) RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5 (2): 438–450.

Rushlow DE, Mol BM, Kennett JY, et al. (2013) Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncology 14 (4): 327–334.

Singh HP, Wang S, Stachelek K, et al. (2018) Developmental stage‐specific proliferation and retinoblastoma genesis in RB‐deficient human but not mouse cone precursors. Proceedings of the National Academy of Sciences of the United States of America 115 (40): E9391–E9400.

Soliman SE, Racher H, Zhang C, MacDonald H and Gallie BL (2017) Genetics and molecular diagnostics in retinoblastoma – an update. Asia‐Pacific Journal of Ophthalmology (Philadelphia, PA) 6: 197–207.

Suckling RD, Fitzgerald PH, Stewart J and Wells E (1982) The incidence and epidemiology of retinoblastoma in New Zealand: a 30‐year survey. British Journal of Cancer 46: 729–736.

Temming P, Arendt M, Viehmann A, et al. (2017) Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: a report from the German reference center. Pediatric Blood & Cancer 64 (1): 71–80.

Xu XL, Fang Y, Lee TC, et al. (2009) Retinoblastoma has properties of a cone precursor tumor and depends upon cone‐specific MDM2 signaling. Cell 137 (6): 1018–1031.

Zhang J, Benavente CA, McEvoy J, et al. (2012) A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481: 329–334.

Further Reading

Benavente CA and Dyer MA (2015) Genetics and epigenetics of human retinoblastoma. Annual Review of Pathology: Mechanisms of Disease 10 (1): 547–562.

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.

Dimaras H, Corson TW, Cobrinik D, et al. (2015) Retinoblastoma. Nature Reviews Disease Primers 1: 15021.

Gallie BL, Campbell C, Devlin H, Duckett A and Squire JA (1999) Developmental basis of retinal‐specific induction of cancer by RB mutation. Cancer Research 59: 1731s–1735s.

Genovese C, Trani D, Caputi M and Claudio PP (2006) Cell cycle control and beyond: emerging roles for the retinoblastoma gene family. Oncogene 25: 5201–5209.

Goodrich DW (2006) The retinoblastoma tumor‐suppressor gene, the exception that proves the rule. Oncogene 25: 5233–5243.

Kaelin WG Jr (1999) Functions of the retinoblastoma protein. BioEssays 21: 950–958.

Knudson AG (2001) Two genetic hits (more or less) to cancer. Nature Reviews Cancer 1: 157–162.

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.

Lohmann DR (1999) RB1 gene mutations in retinoblastoma. Human Mutation 14: 283–288.

Olisa EG, Chandra R, Jackson MA, Kennedy J and Williams AO (1975) Malignant tumors in American black and Nigerian children: a comparative study. Journal of the National Cancer Institute 55: 281–284.

Rushlow D, Piovesan B, Zhang K, et al. (2009) Detection of mosaic RB1 mutations in families with retinoblastoma. Human Mutation 30: 842–851.

Schüler A, Weber S, Neuhäuser M, et al. (2005) Age at diagnosis of isolated unilateral retinoblastoma does not distinguish patients with and without a constitutional RB1 gene mutation but is influenced by a parent‐of‐origin effect. European Journal of Cancer 41: 735–740.

Sherr CJ (2001) The INK4a/ARF network in tumour suppression. Nature Reviews Molecular Cell Biology 2: 731–737.

Sippel KC, Fraioli RE, Smith GD, et al. (1998) Frequency of somatic and germ‐line mosaicism in retinoblastoma: implications for genetic counseling. American Journal of Human Genetics 62: 610–619.

Stengel KR, Thangavel C, Solomon DA, et al. (2009) RB/p107/130 pocket proteins: protein dynamics and interactions with target gene promoters. Journal of Biological Chemistry 284 (29): 19265–19271.

Xu XL, Singh HP, Wang L, et al. (2014) Rb suppresses human cone‐precursor‐derived retinoblastoma tumours. Nature 514 (7522): 385–388.

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(Dec 2018) Genetics of the Pathophysiology of Retinoblastoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006053.pub3]