Retinoblastoma and the Genetic Theory of Cancer: An Old Paradigm Trying to Survive to the Evidence

Abstract

Retinoblastoma (Rb) is considered to represent the prototype of cancer linked to the sequential loss or inactivation of both alleles of a so-called “tumor suppressor gene”, the Rb1 gene. The pathogenetic mechanism behind this tumor was first hypothesized by Knudson in 1971 and further confirmed by others who identified the Rb1 gene whose loss or inactivation was claimed to be responsible for the disease. However, after about four decades of continuous research in the field of molecular biology, the evidence behind the role of the Rb1 gene in Rb appears to be seriously flawed in the light of epidemiological, biological, and clinical evidences. This editorial summarizes the inconsistencies on this subject. Nevertheless, the molecular biology establishment still adheres to the biased view of the genetic origin of Rb and other cancers, and hardly any alternative explanations are taken into account.

13q Deletion syndrome and retinoblastoma in identical dichorionic diamniotic monozygotic twins

“…To our knowledge, this is the first report of dichorionic diamniotic identical monozygotic twins both affected by unilateral retinoblastoma and 13q deletion syndrome, but the cases reported herein also have other relevant implications for a better understanding of the pathogenesis of retinoblastoma and genotype-phenotype correlations. As a matter of fact, as previously reported by us elsewhere (17), there is an evident discrepancy between expected and real incidence of bilateral retinoblastoma among patients affected by the 13q deletion syndrome. The case…”

Retinoblastoma as an Epigenetic Disease: A Proposal

“…On this line of reasoning, we have been able to show herein and elsewhere [16][17][18][19] that the mutational model is largely inadequate to explain the variegated phenotypic expression of retinoblastoma, and there is an increasing agreement among researchers worldwide that the mutational ("two hit") model is outdated and another paradigm has to be adopted for a better understanding of the pathogenesis of retinoblastoma [95].…”

The Epigenetic Origin of Retinoblastoma

“…In a series of previously published papers, [55][56][57][58][59] the authors have argued against the mutation model in Rb, by highlighting the discordance between some of the predictions made by the two hit model and the available clinical data, but did not propose a clear cut alternative to the mutation theory.…”

“…Other clinical phenotypes of the disease include: diffuse infiltrating Rb, 105,106 unilateral and bilateral Rb, 1,7,8,[55][56][57][58][59] and also 'trilateral retinoblastoma', [107][108][109] in which a bilateral Rb is associated with intracranial tumours involving the pineal region.…”