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Retinoblastoma pp 41–54Cite as

Genetics of Retinoblastoma and Genetic Counseling

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Part of the book series: Pediatric Oncology ((PEDIATRICO))

Abstract

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.

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References

  • Braig M, Schmitt CA (2006) Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res 66(6):2881-2884

    Article  PubMed  CAS  Google Scholar 

  • Braig M et al (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436(7051):660-665

    Article  PubMed  CAS  Google Scholar 

  • Buckley JD (1992) The aetiology of cancer in the very young. Br J Cancer Suppl 18:S8-S12

    PubMed  CAS  Google Scholar 

  • Bunin GR et al (1989) Frequency of 13q abnormalities among 203 patients with retinoblastoma. J Natl Cancer Inst 81(5):370-374

    Article  PubMed  CAS  Google Scholar 

  • 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):7129-7133

    PubMed  CAS  Google Scholar 

  • Cavenee WK et al (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305(5937):779-784

    Article  PubMed  CAS  Google Scholar 

  • Chen D, Gallie BL, Squire JA (2001) Minimal regions of chromosomal imbalance in retinoblastoma detected by comparative genomic hybridization. Cancer Genet Cytogenet 129(1):57-63

    Article  PubMed  CAS  Google Scholar 

  • 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):539-551

    Article  PubMed  CAS  Google Scholar 

  • Clarke AR et al (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359(6393):328-330

    Article  PubMed  CAS  Google Scholar 

  • Collado M et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436(7051):642

    Article  PubMed  CAS  Google Scholar 

  • Corson TW, Gallie BL (2007) One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer 46(7):617-634

    Article  PubMed  CAS  Google Scholar 

  • Corson TW et al (2007) KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Clin Cancer Res 13(11):3229-3234

    Article  PubMed  CAS  Google Scholar 

  • 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):6546-6551

    Article  PubMed  Google Scholar 

  • 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 158

    Google Scholar 

  • Dimaras H et al (2006) The loss of p75 neurotrophin receptor expression accompanies malignant progression to human and murine retinoblastoma. Mol Carcinog 45(5):333-343

    Article  PubMed  CAS  Google Scholar 

  • 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):1363-1372

    Google Scholar 

  • Ejima Y et al (1988) Types, rates, origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. Hum Genet 79(2):118-123

    Article  PubMed  CAS  Google Scholar 

  • Eng C et al (1993) Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85(14):1121-1128

    Article  PubMed  CAS  Google Scholar 

  • 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):8-11

    Article  PubMed  Google Scholar 

  • Fletcher O et al (2004) Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 96(5):357-363

    Article  PubMed  Google Scholar 

  • Flexner S (1891) A peculiar glioma (neuroepithelioma?) of the retina. Johns Hopkins Hosp Bull 2:115

    Google Scholar 

  • Gallie BL et al (1982) Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 45(4):513-521

    Article  PubMed  CAS  Google Scholar 

  • Gallie BL et al (1999) Developmental basis of retinal-specific induction of cancer by RB mutation. Cancer Res 59(7 Suppl):1731s-1735s

    PubMed  CAS  Google Scholar 

  • 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):690-694

    Article  PubMed  CAS  Google Scholar 

  • Grasemann C et al (2005) Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene 24(42):6441-6449

    PubMed  CAS  Google Scholar 

  • Griep AE et al (1998) Multiple genetic loci modify risk for retinoblastoma in transgenic mice. Invest Ophthalmol Vis Sci 39(13):2723-2732

    PubMed  CAS  Google Scholar 

  • 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):2952-2957

    Article  PubMed  CAS  Google Scholar 

  • 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):1300-1310

    Article  PubMed  CAS  Google Scholar 

  • 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):1021-1027

    PubMed  CAS  Google Scholar 

  • Jacks T et al (1992) Effects of an Rb mutation in the mouse. Nature 359(6393):295-300

    Article  PubMed  CAS  Google Scholar 

  • 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):1264-1268

    Article  PubMed  Google Scholar 

  • 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):667-668

    Article  PubMed  CAS  Google Scholar 

  • 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):174-179

    Article  PubMed  CAS  Google Scholar 

  • Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68(4):820-823

    Article  PubMed  Google Scholar 

  • Laurie NA et al (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444(7115):61-66

    Article  PubMed  CAS  Google Scholar 

  • Lee EY et al (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359(6393):288-294

    Article  PubMed  CAS  Google Scholar 

  • Lee MH et al (1996) Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev 10(13):1621-1632

    Article  PubMed  CAS  Google Scholar 

  • Lohmann DR (1999) RB1 gene mutations in retinoblastoma. Hum Mutat 14(4):283-288

    Article  PubMed  CAS  Google Scholar 

  • Lohmann DR, Gallie BL (2007) GENE reviews: retino­blastoma http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=retinoblastoma

  • Lohmann D, Scheffer H, Gallie BL (2002) Best practice guidelines for molecular analysis of retinoblastoma. European Molecular Genetics Quality Network (EMQN)

    Google Scholar 

  • MacPherson D et al (2004) Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18(14):1681-1694

    Article  PubMed  CAS  Google Scholar 

  • 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, Toronto

    Google Scholar 

  • Marchong MN et al (2004) Minimal 16q genomic loss implicates cadherin-11 in retinoblastoma. Mol Cancer Res 2(9):495-503

    PubMed  CAS  Google Scholar 

  • Margo C et al (1983) Retinocytoma. A benign variant of retinoblastoma. Arch Ophthalmol 101(10):1519-1531

    Article  PubMed  CAS  Google Scholar 

  • Morgenbesser SD et al (1994) p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 371(6492):72-74

    Article  PubMed  CAS  Google Scholar 

  • Murphree AL (2005) Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am 18:41-53

    Article  Google Scholar 

  • Murray TG et al (1997) Subconjunctival carboplatin therapy and cryotherapy in the treatment of transgenic murine retinoblastoma. Arch Ophthalmol 115(10):1286-1290

    Article  PubMed  CAS  Google Scholar 

  • Ohtani-Fujita N et al (1997) Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet Cytogenet 98(1):43-49

    Article  PubMed  CAS  Google Scholar 

  • Orlic M (2007) Identification of the 6p22 Oncogene in Retinoblastoma, in Molecular and Medical Genetics. University of Toronto, Toronto

    Google Scholar 

  • Orlic M et al (2006) Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer 45(1):72-82

    Article  PubMed  CAS  Google Scholar 

  • 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):293-297

    PubMed  CAS  Google Scholar 

  • Retinoblastoma Solutions Test Sensitivity (2007) Available at: http://www.retinoblastomasolutions.org/testsent.html. Accessed 24 Oct 2007

  • 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):253-269

    Article  PubMed  CAS  Google Scholar 

  • 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):1364-1371

    Article  PubMed  CAS  Google Scholar 

  • Sippel KC et al (1998) Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62(3):610-619

    Article  PubMed  CAS  Google Scholar 

  • Spencer C et al (2005) Distinct patterns of expression of the RB gene family in mouse and human retina. Gene Expr Patterns 5(5):687-694

    Article  PubMed  CAS  Google Scholar 

  • 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):293-304

    Article  PubMed  CAS  Google Scholar 

  • Tso MO (1980) Clues to the cells of origin in retinoblastoma. Int Ophthalmol Clin 20(2):191-210

    PubMed  CAS  Google Scholar 

  • Windle JJ et al (1990) Retinoblastoma in transgenic mice. Nature 343(6259):665-669

    Article  PubMed  CAS  Google Scholar 

  • Wong FL et al (1997) Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278(15):1262-1267

    Article  PubMed  CAS  Google Scholar 

  • 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):793-794

    PubMed  CAS  Google Scholar 

  • Zhang J, Schweers B, Dyer MA (2004) The first knockout mouse model of retinoblastoma. Cell Cycle 3(7):952-959

    Article  PubMed  CAS  Google Scholar 

  • 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):475-484

    Google Scholar 

  • Zhu XP et al (1989) Preferential germline mutation of the paternal allele in retinoblastoma. Nature 340(6231):312-313

    Article  PubMed  CAS  Google Scholar 

  • Zhu X et al (1992) Mechanisms of loss of heterozygosity in retinoblastoma. Cytogenet Cell Genet 59(4):248-252

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Ontario Cancer Institute Princess Margaret Hospital, Toronto, ON, Canada

    H. Dimaras & B. L. Gallie

Authors
  1. H. Dimaras
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  2. B. L. Gallie
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Corresponding author

Correspondence to B. L. Gallie .

Editor information

Editors and Affiliations

  1. Dana-Farber Cancer Institute &, Harvard Medical School, Binney St. 44, Boston, 02115, U.S.A.

    Carlos Rodriguez-Galindo

  2. Hamilton Eye Inst., University of Tennessee, Madison Avenue 930, Memphis, 38103, U.S.A.

    Matthew W. Wilson

Glossary

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.

Expressivity

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.

Mosaic

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

Multifocal retinoblastoma

two or more retinoblastoma tumors affecting one eye.

Penetrance

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

Proband

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.

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Dimaras, H., Gallie, B.L. (2010). Genetics of Retinoblastoma and Genetic Counseling. In: Rodriguez-Galindo, C., Wilson, M. (eds) Retinoblastoma. Pediatric Oncology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-89072-2_4

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  • DOI: https://doi.org/10.1007/978-0-387-89072-2_4

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