Abstract
The causes of retinoblastoma (RB) can now be described with considerable accuracy, although many details are still unclear. Understanding the genetic changes leading to RB has provided an awareness of general mechanisms of cancer development and progression, previously only suspected. From the basic understanding have come new diagnostic technologies that are now ready to be applied directly to RB patients and their families, and a rational approach, based on this understanding, will help us to develop new therapies that avoid the severe complications of conventional treatment.
Similar content being viewed by others
Article PDF
References
Dryja TP, Rapaport JM, Joyce JM, Petersen RA : Molecular detection of deletions involving band q14 of chromosome 13 in retinoblastomas. Proc Natl Acad Sci USA 1986, 83(19): 7391–4.
Friend SH . Bernards R, Rogelj S, et al.: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986, 323 (6089): 643–6.
Dunn JM, Phillips RA, Becker AJ, Gallie BL : Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 1988, 241(4874): 1797–800.
Dunn JM, Phillips RA, Zhu X . Becker AJ, Gallie BL : Mutations in the RB 1 gene and their effects on transcription. Mol. Cell. Biol. 1989, 9: 4594–602.
Yandell DW . Campbell TA, Dayton SH, et al.: Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. New Engl J Med 1989, 321(25): 1689–94.
Ejima Y, Sasaki MS, Kaneko A, Tanooka H : Types, rates origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. Hum Genet 1988, 79(2): 118–23.
Dryja TP, Mukai S . Petersen R, Rapaport JM . Walton D, Yandell DW : Parental origin of mutations of the retinoblastoma gene. Nature 1989, 339: 556–8.
Zhu X, Dunn JM, Goddard AD, et al.: Preferential germline mutation of the paternal allele in retinoblastoma. Nature 1989, 340: 312–13.
Leach RJ, Magewu AN, Buckley JD, et al.: Preferential retention of paternal alleles in human retinoblastoma: evidence for genomic imprinting. Cell Growth Differ 1990, 1(19): 401–6.
Vogel F, and Rathenberg R : Spontaneous mutation in man. Adv Hum Genet 1985, 5: 223–318.
Bunin GR, Meadows AT, Emanuel BS . Buckley JD, Woods WG, Hammond GD: Pre- and postconception factors associated with sporadic heritable and nonheritable retinoblastoma. Cancer Res 1989, 49(20): 5730–5.
Bunin GR . Petrakova A, Meadows AT, et at.: Occupations of parents of children with retinoblastoma: a report from the Children's Cancer Study Group. Cancer Res 1990, 50(22): 7129–33.
Pellie C . Briard ML . Feingold J . Frezal J : Parental age in retinoblastoma. Humangenetik 1973, 20(1): 59–62.
Matsunaga E : Hereditary retinoblastoma: lack of maternal effect. Hum Genet 1982, 62(2): 124–8.
DerKinderen DJ, Koten JW, Tan KE, Beemer FA, Van RLK, Den OW : Parental age in sporadic hereditary retinoblastoma. Am J Ophthalmol 1990, 110(6): 605–9.
Orye E, Delbeke MJ, Vandenabeele B : Retinoblastoma and D-chromosome deletions. Lancet 1971, 2(738): 1376.
Francke U, Kung F : Sporadic bilateral retinoblastoma and 13q-chromosomal deletion. Med Pediatr Onco1 1976, 2(4): 379–85.
Strong LC, Riccardi VM, Ferrell RE, Sparkes RS : Familial retinoblastoma and chromosome 13 deletion transmitted via an insertional translocation. Science 1981, 213(4515): 1501–3.
Horsthemke B, Barnert HJ, Greger V, Passarge E, Höpping W : Early diagnosis in hereditary retinoblastoma by detection of molecular deletions at gene locus. Lancet 1987, 1(8531): 511–2.
Motegi T, Kaga M, Yanagawa Y, et al. A recognizable pattern of the midface of retinoblastoma patients with interstitial delection of 13q. Hum Genet 1983, 64(2): 160–2.
Yunis JJ, Ramsay N : Retinoblastoma and subband deletion of chromosome 13. Am J Dis Child 1978, 132(2): 161–3.
Sparkes RS, Sparkes MC, Wilson MG, et al.: Regional assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science 1980, 208 (4447): 1042–4.
Sparkes RS, Sparkes MC : Esterase D studies in human retinoblastoma. Isozymes Curr Top Biol Med Res 1983, 11: 173–82.
Connolly MJ, Payne RH, Johnson G, et al.: Familial, EsD-linked, retinoblastoma with reduced penetrance and variable expressivity. Hum Genet 1983, 65: 122–4.
McGee TL, Yandell DW, Dryja TP : Structure and partial genomic sequence of the human retinoblastoma susceptibility gene. Gene 1989, 80: 119–28.
Canning S, and Dryja TP : Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene. Proc Natl AcadSci USA 1989, 86: 5044–48.
Lee EY, Bookstein R, Young LJ, Lin CJ, Rosenfeld MG, Lee WH : Molecular mechanism of retinoblastoma gene inactivation in retinoblastoma cell line Y79. Proc. Natl. Acad. Sci. USA 1988, 85(16): 6017–21.
Mitchell CD, and Cowell JK : Predisposition to retinoblastoma due to a translocation within the 4.7R locus. Oncogene 1989, 4(2): 253–7.
Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T : Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Nat'l. Acad. Sci. 1989, 86: 2766–70.
Sakai T, Ohtani N, McGee TL, Robbins PD, Dryja TP : Oncogenic germ-line mutations in Spl and ATF sites in the human retinoblastoma gene. Nature 1991, 353: 83–6.
Godbout R, Dryja TP, Squire J, Gallie BL, Phillips RA : Somatic inactivation of genes on chromosome 13 is a common event in retinoblastoma. Nature 1983, 304(5925): 451–3.
Cavenee WK, Dryja TP, Phillips RA, et al.: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983, 305(5937): 779–84.
Dryja TP, Cavenee W, White R, et al.: Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med 1984, 310 (9): 550–3.
Cavenee WK : Recessive mutant genes predisposing to human cancer. Prog Clin Biol Res 1986, 209A: 575–82.
Zhu X, Dunn JM, Goddard AD, et al.: Mechanisms of Loss of Heterozygosity in Retinoblastoma. Cytogenet and Cell Genet (In press).
Popoff NA, and Ellsworth RM : The fine structure of retinoblastoma. In vivo and in vitro observations. Lab Invest 1971, 25(5): 389–402.
Popoff N, and Ellsworth RM : The fine structure of nuclear alterations in retinoblastoma and in the developing human retina: in vivo and in vitro observations. J Ultrastructure Res 1969, 29: 535–49.
Knudson AGJ : Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971, 68(4): 820–3.
Knudson AGJ, Hethcote HW, Brown BW : Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci USA 1975, 72(12): 5116–20.
Shields CL, Shields JA, Shah P : Retinoblastoma in older children. Ophthalmology 1991, 98(3): 395–9.
Lee WH, Shew JY, Hong FD, et al.: The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature 1987, 329(6140): 642–5.
Buchkovich K, Duffy LA, Harlow E : The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 1989, 58(6): 1097–105.
Chen PL, Scully P, Shew JY, Wang JY, Lee WH : Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentation. Cell 1989, 58(6): 1193–98.
Mihara K, Cao XR, Yen A, et al.: Cell cycle-dependent regulation of phosphorylation of the human retinoblastoma gene product. Science 1989, 246(4935): 1300–3.
Ludlow JW, Shon J, Pipas JM, Livingston DM, De Caprio JA : The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T. Cell 1990, 60(3): 387–96.
Furukawa Y, DeCaprio JA, Freedman A, et al.: Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and noncycling human hematopoietic cells. Proc Natl Acad Sci USA 1990, 87(7): 2770–4.
Thomas NS, Burke LC, Bybee A, Linch DC : The phosphorylation state of the retinoblastoma (RB) protein in G0/G1 is dependent on growth status. Oncogene 1991, 6(2): 317–22.
Lin BT, Gruenwald S, Morla AO, Lee WH, Wang JY : Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase. Embo J 1991, 10(4): 857–64.
Hamel PA, Cohen BL, Sorce LM, Gallie BL, Phillips RA : Hyperphosphorylation of the Retinoblastoma Gene Product is Determined by Domains Outside the SV40 large-T-Binding Regions. Mol. Cell. Biol. 1990, 10: 6586–95.
Whyte P, Buchkovich KJ, Horowitz JM, et al.: Association between an oncogene and an anti-oncogene: the adenovirus EI A proteins bind to the retinoblastoma gene product. Nature 1988, 334(6178): 124–9.
DeCaprio JA, Ludlow JW, Figge J, et al.: SV40 large tumour antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 1988, 54(2): 275–83.
Dyson N, Howley PM, Münger K, Harlow E : The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989, 242: 934–7.
Kaelin WGJ, Ewen ME, Livingston DM : Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in retinoblastoma gene product. Mol Cell Biol 1990, 10(7): 3761–9.
Ludlow JW, DeCaprio JA, Huang C-M, Lee W-H, Paucha E, Livingston DM : SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family. Cell 1989, 56: 57–65.
Kaelin WGJ, Pallas DC, De Caprio JA, Kaye FJ, Livingston DM : Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell 1991, 64(3): 521–32.
Huang S, Lee W-H, Lee EY-HP : A cellular protein that competes with SV40T antigen for binding to the retinoblastoma gene product. 1991, 350: 160–62.
Robbins PD, Horowitz JM, Mulligan RC : Negative regulation of human c-fos expression by the retinoblastoma gene product. Nature 1990, 346: 668–71.
Hamel PA, Gill RM, Phillips RA, Gallie BL : Transcriptional repression of the E2—containing promoters EIIaE, c-myc and RB1 by the product of the RB1 gene. (submitted).
Bandara LR, La Thangue NB : Adenovirus Ela prevents the retinoblastoma gene product from complexing with a cellular transcription factor. Nature 1991, 351: 494–7.
Chellappan SP, Hiebert S, Mudryl M, Horowitz JM, Nevins JR : The E2F transcription factor is a cellular target for the RB protein. Cell 1991, 65: 1053–61.
Bagchi S, Weinmann R, Raychaudhuri P : The retinoblastoma protein copurifies with E2F-I, a ElA-regulated inhibitor of the transcription factor E2F. Cell 1991, 65: 1063–72.
Chittenden T, Livingston DM, Kaelin WG : The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein. Cell 1991, 65: 1073–82.
Huang HJ, Yee JK, Shew JY, et al.: Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 1988, 242(4885): 1563–6.
Bookstein R, Shew J-Y, Chen P-L, Scully P, Lee W-H : Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 1990, 247: 712–15.
Sumegi J, Uzolgyi E, Klein G : Expression of the RB gene under the control of MuLC-LTR suppresses tumorigenicity of WERI-Rb-27 retinoblastoma cells in immunodefective mice. Cell Growth & Differentiation 1990, 1: 247–50.
Muncaster M, Cohen B, Phillips RA, Gallie BL : Failure of RB1 to reverse the malignant phenotype of human tumors cell lines. (submitted).
Horowitz JM, Park SH, Bogenmann E, et al.: Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 1990, 87(7): 2775–9.
Gallie BL, Dunn JM, Chan HS, Hamel PA, Phillips RA : The genetics of retinoblastoma. Relevance to the patient. Pediatr Clin North Am 1991, 38(2): 299–315.
Plotsky D, Quinn G, Eagle R, Shields J, Granowetter L : Congenital retinoblastoma: A case report. J. Ped. Ophthalmol. & Strab. 1987, 24: 120–3.
Gallie BL, Ellsworth RM, Abramson DH, Phillips RA : Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 1982, 45(4): 513–21.
Gallie BL, Phillips RA, Ellsworth RM, Abramson DH : Significance of retinoma and phthisis bulbi for retinoblastoma. Ophthalmology 1982, 89(12): 1393–9.
Abramson DH : Retinoma, retinocytoma, and the retinoblastoma gene [editorial]. Arch Ophthalmol 1983, 101(10): 1517–8.
Squire J, Gallie BL, Phillips RA : A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma. Hum Genet 1985, 70(4): 291–301.
Kusnetsova LE, Prigogina EL, Pogosianz HE, Belkina BM : Similar chromosomal abnormalities in several retinoblastomas. Hum Genet 1982, 61(3): 201–4
Squire J, Phillips RA, Boyce S, Godbout R, Rogers B, Gallie BL : Isochromosome 6p, a unique chromosomal abnormality in retinoblastoma: verification by standard staining techniques, new densitometric methods, and somatic cell hybridization. Hum Genet 1984, 66(1): 46–53.
Kovacs G : Abnormalities of chromosome No. 1 in human solid malignant tumors. Int. J. Cancer 1978, 21: 688–94.
Brito-Babapulle V and Atkin NB : Break points in chromosome #1 abnormalities of 218 human neoplasms. Cancer Genet. Cytogenet. 1981, 4: 215–25.
Sakai K, Tanooka H, Sasaki MS, Ejima Y, Kaneko A : Increase in copy number of N-myc in retinoblastomas in comparison with chromosome abnormality. Cancer Genet Cytogenet 1988, 30(1): 119–26.
Lee WH, Murphree AL, Benedict WF : Expression and amplification of the N-myc gene in primary retinoblastoma. Nature 1984, 309(5967): 458–60.
Wakabayashi K, Atsumi S, Sasabe T, Mori S : Low-amplified N-myc gene and pp60src in retinoblastoma TOTL-1 cells which undergo neuron-like differentiation. Cell Struct Funct 1989, 14(3): 331–43.
Squire J, Goddard AD, Canton M, Becker A, Phillips RA, Gallie BL : Tumour induction by the retinoblastoma mutation is independent of N-myc expression. Nature 1986, 322 (6079): 55–7.
Yokoyama T, Tsukahara T, Nakagawa C, Kikuchi T, Minoda K, Shimatake H : The N-myc gene product in primary retinoblastomas. Cancer 1989, 63(11): 2134–8.
Eagle RCJ, Shields JA, Donoso L, Milner RS : Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 1989, 96(9): 1389–95.
Messmer EP, Heinrich T, Hopping W, de SE, Havers W, Sauerwein W : Risk factors for metastases in patients with retinoblastoma. Ophthalmology 1991, 98(2): 136–41.
de Sutter E, Havers W, Hopping W, Zeller G, Alberti W : The prognosis of retinoblastoma in terms of survival. A computer assisted study. Part II. Ophthalmic Paediatr Genet 1987, 8(2): 85–8.
Petersen RA, Friend SH, Albert DM : Prolonged survival of a child with metastatic retinoblastoma. J Ped Ophthalmol Strabismus 1987, 24: 247–8.
Reese AB, and Ellsworth RM : The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol-Otolaryngol 1963, Mar–Apr: 164–172.
Abramson DH, Ellsworth RM, Kitchin FD, Tung G : Second nonocular tumors in retinoblastoma survivors: Are they radiation-induced? Ophthalmol 1984, 91: 1351–5.
DerKinderen DJ, Koten JW, Nagelkerke NJ, Tan KE, Beemer FA, Den OW : Nonocular cancer in patients with hereditary retinoblastoma and their relatives. Int. J Cancer 1988, 41(4): 499–504.
Draper GJ, Sanders BM, Kingston JE : Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986, 53(5) 661–71.
Roarty JD, McLean IW, Zimmerman LE : Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988, 95(11): 1583–7.
Rothenberg M, and Ling V : Multidrugresistance: molecular biology and clinical relevance. J Natl Cancer Inst 1989, 81(12): 907–10.
Chan SL, Canton MD, Gallic BL : Chemosensitivity and multidrug resistance to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res. 1989, 9: 469–74.
Twentyman PR, Fox NE, White DJ : Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multi-drug resistant human lung cancer cell line. Br J Cancer 1987, 56(1): 55–7.
Durie BG and Dalton WS : Reversal of drug-resistance in multiple myeloma with verapamil. Br J Haematol 1988, 68(2): 203–6.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gallie, B., Dunn, J., Hamel, P. et al. How do retinoblastoma tumours form?. Eye 6, 226–231 (1992). https://doi.org/10.1038/eye.1992.44
Issue Date:
DOI: https://doi.org/10.1038/eye.1992.44