Genetics of Retinoblastoma and Genetic Counseling

Part of the Pediatric Oncology book series (PEDIATRICO)


Retinoblastoma was the first cancer to be described as a genetic disease. The progression of a normal retinal cell to the eventual malignant tumor involves a step-wise accumulation of molecular genetic alterations, which correlate with clinical stage and pathology of the tumor. This chapter gives an overview of the current state of knowledge of retinoblastoma genetics and its implications for genetic counseling.


Genetic Counseling Retinoblastoma Tumor Human Retinoblastoma Retinoblastoma Cell Line Retinoblastoma Patient 



Bilateral retinoblastoma

retinoblastoma that affects both eyes.

de novo germline mutation

new mutation, arising ­sporadically in a germ cell of the proband’s parent or in early stages of embryogenesis of the proband.


the phenotypic heterogeneity in the presentation of the disease.

Familial retinoblastoma

the RB1 allele that resulted in retinoblastoma was transmitted from a parent; children with familial retinoblastoma are constitutionally heterozygous for RB1 mutant alleles.

Heritable retinoblastoma

offspring of probands with heritable retinoblastoma are at 50% risk to inherit the mutant allele.

Isolated or sporadic retinoblastoma

no family history of retinoblastoma; may or may not have a constitutional RB1 mutant allele.


the RB1 mutation occurred early in development, affecting only a subset of constitutional cells.

Multifocal retinoblastoma

two or more retinoblastoma tumors affecting one eye.


the frequency at which a genotype (mutation) is expressed at the phenotypic level.


the first patient in a family to be diagnosed with retinoblastoma.

Trilateral retinoblastoma

retinoblastoma develops in both eyes (or only one eye) in addition to pinealoblastoma or a primitive neuroectodermal brain tumor.

Unifocal retinoblastoma

a single retinoblastoma tumor in one eye.

Unilateral retinoblastoma

retinoblastoma that affects one eye.


  1. Braig M, Schmitt CA (2006) Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res 66(6):2881-2884PubMedCrossRefGoogle Scholar
  2. Braig M et al (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436(7051):660-665PubMedCrossRefGoogle Scholar
  3. Buckley JD (1992) The aetiology of cancer in the very young. Br J Cancer Suppl 18:S8-S12PubMedGoogle Scholar
  4. Bunin GR et al (1989) Frequency of 13q abnormalities among 203 patients with retinoblastoma. J Natl Cancer Inst 81(5):370-374PubMedCrossRefGoogle Scholar
  5. Bunin GR et al (1990) Occupations of parents of children with retinoblastoma: a report from the Children’s Cancer Study Group. Cancer Res 50(22):7129-7133PubMedGoogle Scholar
  6. Cavenee WK et al (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305(5937):779-784PubMedCrossRefGoogle Scholar
  7. Chen D, Gallie BL, Squire JA (2001) Minimal regions of chromosomal imbalance in retinoblastoma detected by comparative genomic hybridization. Cancer Genet Cytogenet 129(1):57-63PubMedCrossRefGoogle Scholar
  8. Chen D et al (2004) Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 5(6):539-551PubMedCrossRefGoogle Scholar
  9. Clarke AR et al (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359(6393):328-330PubMedCrossRefGoogle Scholar
  10. Collado M et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436(7051):642PubMedCrossRefGoogle Scholar
  11. Corson TW, Gallie BL (2007) One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer 46(7):617-634PubMedCrossRefGoogle Scholar
  12. Corson TW et al (2007) KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Clin Cancer Res 13(11):3229-3234PubMedCrossRefGoogle Scholar
  13. de Bruin A et al (2003) Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice. Proc Natl Acad Sci U S A 100(11):6546-6551PubMedCrossRefGoogle Scholar
  14. Dimaras H (2007) The molecular progression from retina through retinoma to retinoblastoma and the role of the p75NTR neurotrophin receptor, Department of Molecular and Medical Genetics. University of Toronto, Toronto, p 158Google Scholar
  15. Dimaras H et al (2006) The loss of p75 neurotrophin receptor expression accompanies malignant progression to human and murine retinoblastoma. Mol Carcinog 45(5):333-343PubMedCrossRefGoogle Scholar
  16. Dimaras H et al (2008) Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hom Mol Genet 17(10):1363-1372Google Scholar
  17. Ejima Y et al (1988) Types, rates, origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. Hum Genet 79(2):118-123PubMedCrossRefGoogle Scholar
  18. Eng C et al (1993) Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85(14):1121-1128PubMedCrossRefGoogle Scholar
  19. Escalona-Benz E et al (2005) Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma. Invest Ophthalmol Vis Sci 46(1):8-11PubMedCrossRefGoogle Scholar
  20. Fletcher O et al (2004) Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 96(5):357-363PubMedCrossRefGoogle Scholar
  21. Flexner S (1891) A peculiar glioma (neuroepithelioma?) of the retina. Johns Hopkins Hosp Bull 2:115Google Scholar
  22. Gallie BL et al (1982) Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 45(4):513-521PubMedCrossRefGoogle Scholar
  23. Gallie BL et al (1999) Developmental basis of retinal-specific induction of cancer by RB mutation. Cancer Res 59(7 Suppl):1731s-1735sPubMedGoogle Scholar
  24. Genuardi M et al (2001) Multiple lipomas linked to an RB1 gene mutation in a large pedigree with low penetrance retinoblastoma. Eur J Hum Genet 9(9):690-694PubMedCrossRefGoogle Scholar
  25. Grasemann C et al (2005) Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene 24(42):6441-6449PubMedGoogle Scholar
  26. Griep AE et al (1998) Multiple genetic loci modify risk for retinoblastoma in transgenic mice. Invest Ophthalmol Vis Sci 39(13):2723-2732PubMedGoogle Scholar
  27. Hagstrom SA, Dryja TP (1999) Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas. Proc Natl Acad Sci U S A 96(6):2952-2957PubMedCrossRefGoogle Scholar
  28. Howes KA et al (1994) Apoptosis or retinoblastoma: alternative fates of photoreceptors expressing the HPV-16 E7 gene in the presence or absence of p53. Genes Dev 8(11):1300-1310PubMedCrossRefGoogle Scholar
  29. Hu N et al (1994) Heterozygous Rb-1 delta 20/+mice are ­predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9(4):1021-1027PubMedGoogle Scholar
  30. Jacks T et al (1992) Effects of an Rb mutation in the mouse. Nature 359(6393):295-300PubMedCrossRefGoogle Scholar
  31. Jockovich ME et al (2006) Anecortave acetate as single and adjuvant therapy in the treatment of retinal tumors of LH(BETA)T(AG) mice. Invest Ophthalmol Vis Sci 47(4):1264-1268PubMedCrossRefGoogle Scholar
  32. Klutz M, Horsthemke B, Lohmann DR (1999) RB1 gene mutations in peripheral blood DNA of patients with isolated unilateral retinoblastoma. Am J Hum Genet 64(2):667-668PubMedCrossRefGoogle Scholar
  33. Klutz M, Brockmann D, Lohmann DR (2002) A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene. Am J Hum Genet 71(1):174-179PubMedCrossRefGoogle Scholar
  34. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68(4):820-823PubMedCrossRefGoogle Scholar
  35. Laurie NA et al (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444(7115):61-66PubMedCrossRefGoogle Scholar
  36. Lee EY et al (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359(6393):288-294PubMedCrossRefGoogle Scholar
  37. Lee MH et al (1996) Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev 10(13):1621-1632PubMedCrossRefGoogle Scholar
  38. Lohmann DR (1999) RB1 gene mutations in retinoblastoma. Hum Mutat 14(4):283-288PubMedCrossRefGoogle Scholar
  39. Lohmann DR, Gallie BL (2007) GENE reviews: retino­blastoma
  40. Lohmann D, Scheffer H, Gallie BL (2002) Best practice guidelines for molecular analysis of retinoblastoma. European Molecular Genetics Quality Network (EMQN)Google Scholar
  41. MacPherson D et al (2004) Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18(14):1681-1694PubMedCrossRefGoogle Scholar
  42. Marchong MN (2007) Identification of CDH11 as a candidate tumor suppressor in retinoblastoma and characterization of its role in retina and retinoblastoma, Department of Medical Biophysics. University of Toronto, TorontoGoogle Scholar
  43. Marchong MN et al (2004) Minimal 16q genomic loss implicates cadherin-11 in retinoblastoma. Mol Cancer Res 2(9):495-503PubMedGoogle Scholar
  44. Margo C et al (1983) Retinocytoma. A benign variant of retinoblastoma. Arch Ophthalmol 101(10):1519-1531PubMedCrossRefGoogle Scholar
  45. Morgenbesser SD et al (1994) p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 371(6492):72-74PubMedCrossRefGoogle Scholar
  46. Murphree AL (2005) Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am 18:41-53CrossRefGoogle Scholar
  47. Murray TG et al (1997) Subconjunctival carboplatin therapy and cryotherapy in the treatment of transgenic murine retinoblastoma. Arch Ophthalmol 115(10):1286-1290PubMedCrossRefGoogle Scholar
  48. Ohtani-Fujita N et al (1997) Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet Cytogenet 98(1):43-49PubMedCrossRefGoogle Scholar
  49. Orlic M (2007) Identification of the 6p22 Oncogene in Retinoblastoma, in Molecular and Medical Genetics. University of Toronto, TorontoGoogle Scholar
  50. Orlic M et al (2006) Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer 45(1):72-82PubMedCrossRefGoogle Scholar
  51. Radhi JM (1999) Malignant melanoma arising from nevi, p53, p16, and Bcl-2: expression in benign versus malignant components. J Cutan Med Surg 3(6):293-297PubMedGoogle Scholar
  52. Retinoblastoma Solutions Test Sensitivity (2007) Available at: Accessed 24 Oct 2007
  53. Richter S et al (2003) Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet 72(2):253-269PubMedCrossRefGoogle Scholar
  54. Sabah M et al (2004) Loss of heterozygosity of chromosome 9p and loss of p16INK4A expression are associated with malignant gastrointestinal stromal tumors. Mod Pathol 17(11):1364-1371PubMedCrossRefGoogle Scholar
  55. Sippel KC et al (1998) Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62(3):610-619PubMedCrossRefGoogle Scholar
  56. Spencer C et al (2005) Distinct patterns of expression of the RB gene family in mouse and human retina. Gene Expr Patterns 5(5):687-694PubMedCrossRefGoogle Scholar
  57. Tsai KY et al (1998) Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 2(3):293-304PubMedCrossRefGoogle Scholar
  58. Tso MO (1980) Clues to the cells of origin in retinoblastoma. Int Ophthalmol Clin 20(2):191-210PubMedGoogle Scholar
  59. Windle JJ et al (1990) Retinoblastoma in transgenic mice. Nature 343(6259):665-669PubMedCrossRefGoogle Scholar
  60. Wong FL et al (1997) Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278(15):1262-1267PubMedCrossRefGoogle Scholar
  61. Zeschnigk M, Lohmann D, Horsthemke B (1999) A PCR test for the detection of hypermethylated alleles at the retinoblastoma locus. J Med Genet 36(10):793-794PubMedGoogle Scholar
  62. Zhang J, Schweers B, Dyer MA (2004) The first knockout mouse model of retinoblastoma. Cell Cycle 3(7):952-959PubMedCrossRefGoogle Scholar
  63. Zhang K et al. (2008) Patterns of missplicing caused by RB1 gene mutations in patients with retinoblastoma and association with phenotypic expression. Hum Mutat. 29(4):475-484Google Scholar
  64. Zhu XP et al (1989) Preferential germline mutation of the paternal allele in retinoblastoma. Nature 340(6231):312-313PubMedCrossRefGoogle Scholar
  65. Zhu X et al (1992) Mechanisms of loss of heterozygosity in retinoblastoma. Cytogenet Cell Genet 59(4):248-252PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Ontario Cancer Institute Princess Margaret HospitalTorontoCanada

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