Advertisement

Biology of Retinoblastoma

  • Michael A. Dyer
Chapter
Part of the Pediatric Oncology book series (PEDIATRICO)

Abstract

Studies on retinoblastoma have led to several landmark studies in cancer genetics over the past 4 decades. In 1971, Knudson proposed that retinoblastoma might initiate by biallelic inactivation of a putative tumor suppressor gene (Knudson 1971). This “two-hit hypothesis” was based on the observation that there were two distinct forms of retinoblastoma seen in the clinic. Children with a family history of retinoblastoma often had bilateral multifocal retinoblastoma. In contrast, children with unilateral retinoblastoma rarely had any family history of the disease. Knudson proposed that for retinoblastoma to form, both copies of a putative tumor suppressor gene had to be inactivated. Children with a family history of retinoblastoma inherited a defective copy of this tumor suppressor gene and were likely to have retinal cells that sustained mutations in the second allele, leading to multifocal bilateral retinoblastoma. In contrast, children who have two intact copies of the retinoblastoma susceptibility gene develop retinoblastoma only when a single cell sustains two independent mutations that inactivate both copies of the gene. The lower probability of two inactivating mutations in the retinoblastoma susceptibility gene could account for the observation that these children often had unilateral retinoblastoma with fewer tumor foci.

Several years later, Weinberg’s lab cloned Knudson’s putative tumor suppressor gene by studying genetic lesions and chromosomal aberrations in families with a history of retinoblastoma (Friend et al. 1986). This was the first human tumor suppressor gene to be cloned and it was named RB1 (Friend et al. 1986). Initially, researchers believed that RB1 was important for retinoblastoma susceptibility, but its role in other human cancers was unknown until Harbour and colleagues found that the RB1 gene was also mutated in lung cancer (Harbour et al. 1988). Today, it is widely held that most, if not all, tumors have sustained genetic lesions in their Rb pathway that contribute to deregulated cellular proliferation. These landmark studies on the genetics of retinoblastoma susceptibility have had a major impact on our understanding of tumor suppressor genes and have formed the framework for much of our current knowledge of genetic lesions associated with tumorigenesis.

Keywords

Genetic Lesion Tumor Suppressor Pathway Retinal Progenitor Cell Putative Tumor Suppressor Gene Human Retinoblastoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Ajioka I et al (2007) Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 131(2):378PubMedCrossRefGoogle Scholar
  2. Aslanian A, Iaquinta PJ, Verona R, Lees JA (2004) Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Genes Dev 18(12):1413PubMedCrossRefGoogle Scholar
  3. 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):539PubMedCrossRefGoogle Scholar
  4. Clarke AR et al (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359(6393):328PubMedCrossRefGoogle Scholar
  5. Donovan SL et al (2006) Compensation by tumor suppressor genes during retinal development in mice and humans. BMC Biol 4:14PubMedCrossRefGoogle Scholar
  6. Dyer MA, Bremner R (2005) The search for the retinoblastoma cell of origin. Nat Rev Cancer 5(2):91PubMedGoogle Scholar
  7. Friend SH et al (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323(6089):643PubMedCrossRefGoogle Scholar
  8. Harbour JW et al (1988) Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241(4863):353PubMedCrossRefGoogle Scholar
  9. Jacks T et al (1992) Effects of an Rb mutation in the mouse. Nature 359(6393):295PubMedCrossRefGoogle Scholar
  10. Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. PNAS 68:820Google Scholar
  11. Laurie NA et al (2005) Topotecan combination chemotherapy in two new rodent models of retinoblastoma. Clin Cancer Res 11(20):7569PubMedCrossRefGoogle Scholar
  12. Laurie NA et al (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444(7115):61PubMedCrossRefGoogle Scholar
  13. Lee EY et al (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359(6393):288PubMedCrossRefGoogle Scholar
  14. Maandag EC et al (1994) Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J 13(18):4260PubMedGoogle Scholar
  15. Macpherson D, Dyer MA (2007) Retinoblastoma: from the two-hit hypothesis to targeted chemotherapy. Cancer Res 67(16):7547PubMedCrossRefGoogle Scholar
  16. MacPherson D et al (2004) Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18(14):1681PubMedCrossRefGoogle Scholar
  17. Marine JC, Dyer MA, Jochemsen AG (2007) MDMX: from bench to bedside. J Cell Sci 120(Pt 3):371PubMedCrossRefGoogle Scholar
  18. O’Brien JM et al (1990) A transgenic mouse model for trilateral retinoblastoma. Arch Ophthalmol 108(8):1145PubMedCrossRefGoogle Scholar
  19. Robanus-Maandag E et al (1998) p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 12(11):1599PubMedCrossRefGoogle Scholar
  20. Vooijs M, te Riele H, van der Valk M, Berns A (2002) Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinol binding protein-expressing cells. Oncogene 21(30):4635Google Scholar
  21. Zhang J, Schweers B, Dyer MA (2004) The first knockout mouse model of retinoblastoma. Cell Cycle 3(7):952PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Developmental NeurobiologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations