Abstract
The aim of the present chapter is to gi e new insights into the pathogenesis of retinoblastoma, by applying the principles of epigenetics to the analysis of clinical, epidemiological, and biological data concerning the disease. As an emerging new scientific approach linking the genome to the environment, epigenetics, when applied to the interpretation of clinical, epidemiological, and biological data in retinoblastoma, can explain not only the inconsistencies of the mutational (“two hit”) model, but also open new outstanding scenarios in this fields of diagnosis, treatment and prevention of this eye tumor, and cancer in general. After more than four decades of predominance of the genetic theory, this chapter represents the first attempt to look at retinoblastoma from the point of view of epigenetics. The epigenetic model in the genesis of retinoblastoma, proposed herein, emphasizes the role of environment and the interaction of the environment with the genome, in generating retinoblastoma in young children. Environmental toxicants, including radiations, wrong diets, and infectious diseases, play a major role in conditioning the degree of DNA methylation (one of the leading mechanisms of epigenetic gene modulation) in embryos and fetuses during pregnancy, thus leading to stable, functional alterations of the genome, which, on the other hand, can also be transmitted from one generation to the next, thus mimicking a hereditary disease. An accurate analysis of the currently available literature on both retinoblastoma and epigenetics, coupled with the knowledge of the variegated phenotypic expression of the disease, can easily lead to the conclusion that retinoblastoma is an epigenetic, rather than a genetic disease.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Barbosa RH, Vargas FR, Aguiar FC, Ferman S, Lucena E, Bonvicino CR, Seuánez HN (2008) Hereditary retinoblastoma transmitted by maternal germline mosaicism. Pediatr Blood Cancer 51:598–602
Berkow RL, Fleshman JK (1983) Retinoblastoma in Navajo Indian children. Am J Dis Child 137:137–138
Brugge D, Goble R (2002) The history of uranium mining and the Navajo people. Am J Pub Health 92:1410–1419
Buiting K, Kanber D, Lohmann D (2010) Imprinting of Rb1 (the new kid on the block). Brief Funct Genomics 9:347–353
Chinnam M, Goodrich DW (2011) Rb1, development and cancer. Curr Top Dev Biol 94:129–156
Costa FF (2010) Epigenomics in cancer management. Cancer Manag Res 2:255–265
Dolinoy C, Jirtle RL (2008) Environmental epigenomics in human health and disease. Environ Mol Mutagen 49:4–8
Dolinoy DC, Wiedman J, Waterland R, Jirtle RL (2006) Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114:567–572
Dolinoy C, Weidman JR, Jirtle RL (2007a) Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 23:297–307
Dolinoy DC, Das R, Weidman JR, Jirtle RL (2007b) Metastable epialleles, imprinting, and the fetal origins of adult diseases. Pediatr Res 61:31–37
Duesberg P (2007) Chromosomal chaos and cancer. Sci Am 296:52–59
Eagle RC, Shields JA, Donoso L, Milner RS (1989) Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 96:1389–1395
Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440
Franklin TB, Mansuy IM (2010) Epigenetic inheritance in mammals: evidence for the impact of adverse environmental effects. Neurobiol Dis 39:61–65
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–646
Greger V, Passarge E, Höpping W, Messmer B, Horsthemke B (1989) Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 83:155–158
Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Minna JD, Gazdar AF (2002a) Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene 21:4345–4349
Harada K, Toyooka S, Shivapurkar N, Maitra A, Reddy JL, Matta H, Miyajima K, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Chaudhary PM, Gazdar AF (2002b) Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res 62:5897–5901
Hernando E, Nahlé Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M, Michel L, Mittal V, Gerald W, Benezra R, Lowe SW, Cordon-Cardo C (2004) Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430:797–802
Holliday R, Pugh JC (1975) DNA modification mechanisms and gene activity during development. Science 187:226–232
Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262
Knudson G (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823
Lohmann R, Gallie BL (2010) Retinoblastoma. In: Pagon RA, Bird TC, Dolan CR, Stephens K (eds) Gene reviews. University of Washington, Seattle
Mastrangelo D, De Francesco S, Di Leonardo A, Lentini L, Hadjistilianou T (2008) The retinoblastoma paradigm revisited. Med Sci Monit 14:231–240
Nichols KE, Walther S, Chao E, Shields C, Ganguly A (2009) Recent advances in retinoblastoma genetic research. Curr Opin Ophthalmol 20:351–355
Poulaki V, Mitsiades CS, Kotoula V, Negri J, McMullan C, Millar JW, Marks PA, Mitsiades N (2008) Molecular sequelae of histone deacetylase inhibition in human retinoblastoma cell lines: clinical implications. IOVS 50: 4072–4079
Rathi A, Virmani AK, Harada K, Timmons CF, Miyajima K, Hay RJ, Mastrangelo D, Maitra A, Tomlinson GE, Gazdar AF (2003) Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clin Cancer Res 9:3674–3678
Rushlow D, Piovesan B, Zhang K, Prigoda-Lee NL, Marchong MN, Clark RD, Gallie BL (2009) Detection of mosaic Rb1 mutations in families with retinoblastoma. Hum Mutat 30:842–851
Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36
Shigematsu H, Suzuki M, Takahashi T, Miyajima K, Toyooka S, Shivapurkar N, Tomlinson GE, Mastrangelo D, Pass HI, Brambilla E, Sathyanarayana UG, Czerniak B, Fujisawa T, Shimizu N, Gazdar AF (2005) Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies. Int J Cancer 113:600–604
Sippel KC, Fraioli RE, Smith GD, Schalkoff ME, Sutherland J, Gallie BL, Dryja TP (1998) Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62:610–619
Steward JK, Smith JLS, Arnold EL (1956) Spontaneous regression of retinoblastoma. Br J Ophthalmol 40:449–461
Stiller CA (1993) Retinoblastoma and low level of radiation. Br Med J 307:461–462
Taby R, Issa JPJ (2010) Cancer epigenetics. CA Cancer J Clin 60:376–392
Waddington H (1940) Organisers and genes. Cambridge University Press, Cambridge
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Mastrangelo, D., Loré, C., Grasso, G. (2012). Retinoblastoma Epigenetics. In: Hayat, M. (eds) Tumors of the Central Nervous System, Volume 8. Tumors of the Central Nervous System, vol 8. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4213-0_13
Download citation
DOI: https://doi.org/10.1007/978-94-007-4213-0_13
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-4212-3
Online ISBN: 978-94-007-4213-0
eBook Packages: MedicineMedicine (R0)