Retinoblastoma epidemiology: Does the evidence matter? D. Mastrangelo a, *, S. De Francesco a , A. Di Leonardo b , L. Lentini b , T. Hadjistilianou a a Department of Ophthalmology, Ocular Oncology Unit, University of Siena, Policlinico Le Scotte, Viale Bracci 2, 53100 Siena, Italy b Department of Cell and Developmental Biology ‘A. Monroy’, Palermo, Italy ARTICLE INFO Article history: Received 18 January 2007 Received in revised form 17 March 2007 Accepted 19 April 2007 Available online 31 May 2007 Keywords: Retinoblastoma Aneuploidy Two hit theory Microsatellite instability Chromosome instability Epigenetic ABSTRACT It has been proposed that retinoblastoma is ‘caused’ by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic altera- tions. Retinoblastoma remains probably the only cancer in which the rather simplistic ‘two hit’ mutational model is still considered of value, although cancer is known to be associated with genomic and microsatellite instability, defects of the DNA mismatch repair system, alterations of DNA methylation and hystone acethylation/deacethylation, and aneuploidy. Moreover, as it is shown herein, the predictions made by the ‘two hit’ model, are not ful- filled by the clinical and epidemiological data reported so far. Moreover, while the role of mutational events in cancer has been largely questioned in the more recent literature, no serious effort has been done to investigate the role of epigenetic alterations and aneu- ploidy in retinoblastoma. Through the analysis of the specialised literature and a set of original epidemiological and biological data concerning retinoblastoma, the authors illustrate the evidences arguing against the ‘two hit’ hypothesis and propose that epigenetic factors and aneuploidy play central roles in the disease. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Retinoblastoma (Rb) is a tumour affecting the retina of one (unilateral Rb) or both eyes (bilateral Rb) in children. Enucle- ation (i.e. the surgical ablation of the affected eye), with con- sequent blindness, still represents a common modality in the management of the disease, even if more ‘conservative’ ap- proaches have become increasingly practiced in recent years, thanks to the availability of newer and more sophisticated lo- cal treatment modalities. 1 A large amount of highly specialised information on reti- noblastoma is presently available through the Internet and at easy reach by anyone wanting to get detailed information on this eye tumour affecting young children. However, the honourable purpose of spreading informa- tion that can be invaluable for affected patients and their par- ents, should not lead to disregarding the absolute necessity of a strict control on the quality and reliability of the informa- tion itself, particularly when the ‘audience’ is as large as that of the worldwide web users. A closer look at the information reported on retinoblas- toma by some groups of qualified scientists in this field, gives us the opportunity to discuss some of the statements, concepts and ideas regarding this disease that, to our opin- ion, are far from being definitively demonstrated and accepted. One example is represented by the definition of the role of the RB1 gene in retinoblastoma. As reported in one of 0959-8049/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2007.04.019 * Corresponding author: Tel.: +39 577 369101; fax: +39 577 369185. E-mail address: mastrangelo@unisi.it (D. Mastrangelo). EUROPEAN JOURNAL OF CANCER 43 (2007) 1596 – 1603 available at www.sciencedirect.com journal homepage: www.ejconline.com