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Posterior Segment Retinoblastoma The Epigenetic Origin of Retinoblastoma Domenico Mastrangelo, 1 Cosimo Loré 2 and Giovanni Grasso 3 1. Senior Scientist, Research; 2. Full Professor; 3. Full Professor of Anatomy and Biology, University of Siena, Italy Abstract The aim of the present review is to give new insights into the pathogenesis of retinoblastoma, by applying the principles of epigenetics to the study of clinical, epidemiological and biological data concerning the disease. As an emerging new scientific approach linking the genome to the environment, epigenetics, can not only explain the inconsistencies of the mutational (‘two hit’) model in the genesis of retinoblastoma, but also open new outstanding scenarios in the fields of diagnosis, treatment and prevention of this eye tumour and cancer in general. After more than four decades of predominance of the ‘genetic’ theory, this review represents, to the authors’ knowledge, the first attempt to look at retinoblastoma from the point of view of epigenetics. The epigenetic model in the genesis of retinoblastoma, proposed herein, emphasises the role of environment and its interactions with the genome, in generating retinoblastoma in young children. Environmental toxicants, including, among others, radiations, wrong diets and infectious diseases, all play a major role in conditioning the degree of DNA methylation (one of the leading mechanisms of epigenetic gene regulation) in embryos and foetuses during pregnancy, thus leading to stable, functional alterations of the genome, which can 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. Keywords Retinoblastoma, epigenetics, DNA methylation, histone acetylation/deacetylation Disclosure: The authors have no conflicts of interest to declare. Received: 6 December 2011 Accepted: 2 February 2012 Citation: European Ophthalmic Review, 2012;6(2):130–5 Correspondence: Domenico Mastrangelo, Department of Biomedical Sciences, University of Siena, Polo Scientifico “San Miniato”, Viale Aldo Moro, 53100 Siena, Italy. E: About ‘Causation’ in Retinoblastoma Since the formulation of the ‘two hit’ hypothesis in the genesis of retinoblastoma (Rb), 1 there has been widespread agreement, among researchers in the field of ocular oncology, that this eye tumour is determined by the loss, mutation or inactivation of both copies of one and a single gene. The gene was later identified and denominated Rb1, 2 and this discovery opened the ‘hunting’ to the inactivating mutation/s ‘causing’ Rb. The ‘causative’ role of the Rb1 gene mutations in Rb, is no longer a matter of discussion, among the vast majority of researchers worldwide, as it is clearly stated in both the most recent scientific papers 3–5 and institutional information 6–10 concerning the disease. However, it is widely recognised that the ‘cause’ of most (if not all) cancers is still unknown and the ‘mutation theory’ only tells us about a possible pathogenetic mechanism (the alteration of the DNA structure of the genome) presumably involved in the genesis of Rb. Nevertheless, the question about what ultimately ‘causes’ the mutations, which lead to cancer development in Rb (and in cancer, in general), remains unanswered. Moreover, the role of gene mutations in the genesis of cancer, has been largely questioned by scientists who have remarked, among others, the fact that carcinogens do exist, as pesticides, 11 phenobarbital and clofibrate, 12 tumour promoters (1,4-dichlorobenzene), endocrine-modifiers (17β-estradiol), receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin), 130 immune suppressants (cyclosporine) or inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium), among others, which are not genotoxic and therefore must be assumed to induce cancer without producing gene mutations. 13–17 These non-genotoxic (or ‘epigenetic’) carcinogens are well-known chemicals which induce cancer without modifying the DNA structure and nucleotide sequence of the human genome, 18 and represent the strongest argument against the role of gene mutation as the only pathogenetic mechanism leading to cancer. However, the arguments against the role of gene mutations in cancer abound in the literature 19–27 even though a detailed discussion of this matter goes beyond the scope of the present review. In summary, the awareness that gene mutations are only part of the process through which normal cells become cancerous, the other being represented by epigenetic (and ‘non-structural’) gene modifications, should suggest more caution in attributing a causative role to a mutation affecting one and a single gene, as it has been the case of Rb, after the first formulation of the two hit hypothesis, proposed by Knudson in 1971. Epigenetics – The New Frontier in Cancer The term ‘Epigenetics’ was coined in 1940 by Conrad Waddington to designate, “… the interactions of genes with their environment which bring the phenotype into being”, 28,29 thus clearly indicating that © TOUCH BRIEFINGS 2012