Retinoblastoma epidemiology: Does the evidence matter?

Abstract

AneuploidyTwo hit theory Microsatellite instabilityChromosome instability Epigenetic A B S T R A C T 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been proposed that retinoblastoma is 'caused' by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations.Retinoblastoma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 fulfilled 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 aneuploidy 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.

Recent advances in retinoblastoma genetic research

“…Recently, Mastrangelo et al and others proposed an alternative hypothesis that 'aneuploidy' (i.e. gains or losses of different regions of the genome and/or epigenetic alterations), and not RB1 inactivation per se, is what initiates to retinoblastoma tumor formation [18][19][20]. Aneuploidy and RB1 inactivation are not mutually exclusive.…”

Molecular Sequelae of Histone Deacetylase Inhibition in Human Retinoblastoma Cell Lines: Clinical Implications

“…The "two-hit" theory of RB1 inactivation during retinoblastoma development was proposed by Knudson in 1971 5 and has been widely accepted, though recent data have emphasized the importance of additional epigenetic events, genomic instability, and aneuploidy. 2,6,7 A major mechanism of epigenetic regulation of gene expression is by control of the level of acetylation on lysine residues of the amino-terminal tails of histones through the opposing activities of histone deacetylases (HDACs) and histone acetyltransferases (HATs). 8 In general, chromatin composed of nucleosomes in which the histones have low levels of acetylation is more likely to be transcriptionally silent.…”

Genes and environment: effects on the development of second malignancies in retinoblastoma survivors

“…Recently, several authors have argued that genomic instability, microsatellite instability, defects of the DNA mismatch repair system, and alterations in DNA methylation and acethylation/ deacethylation may be primarily responsible for the genesis of retinoblastoma, rather than mutations in the rb1 gene [16,17]. These authors argue that the epidemiologic patterns of unilateral versus bilateral and familial versus nonfamilial disease do not support the long-held concept that retinoblastoma is a genetic disease, but rather an epigenetic phenomenon.…”