A Personal Sixty-Year Tour of Genetics and Medicine

Knudson, Alfred G.

doi:10.1146/annurev.genom.6.080604.162320

Cited by 14 publications

(7 citation statements)

References 41 publications

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“…The theory illustrating the relationship between the timing and the target of the first and second 'hit', on one side, and the age distribution of retinoblastoma, as related to its inherited or sporadic nature, on the other, has been further detailed and explained in a number of publications by the same author, [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and is presently a consolidated and accepted view among scientists worldwide. Fig.…”

Section: Resultsmentioning

confidence: 99%

Retinoblastoma epidemiology: Does the evidence matter?

Milardi

Francesco

Leonardo³

et al. 2007

European Journal of Cancer

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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been proposed that retinoblastoma is 'caused' by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations.Retinoblastoma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.

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Section: Resultsmentioning

confidence: 99%

Retinoblastoma epidemiology: Does the evidence matter?

Milardi

Francesco

Leonardo³

et al. 2007

European Journal of Cancer

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“…2) can be found in either affected patients and their unaffected parents [73], and 3) can involves both the paternal and maternal germ-line [74]. Both phenotypic variation and cellular mosaicism, although quite common in retinoblastoma, are unexplainable in the light of the mutational model which assumes that when the first mutation is inherited through the germline, all the somatic and germ cells of the individual will carry that mutation [2,6,7].…”

Section: Retinoblastoma Metastable Epialleles and Transposable Genementioning

confidence: 99%

“…Knudson's mutational model, maintains that two sequential mutations of the Rb1 gene are necessary to develop a retinoblastoma, and the timing and target of these two mutational events determines the clinical phenotype of the disease. Namely, when both the first and second mutations involve the somatic cells, the individual will develop a tumour affecting only one eye (unilateral retinoblastoma), but when the first mutation occurs in the germinal cells of one parent, and the second involves the individual's somatic retinal cells, the disease will affect both eyes (bilateral retinoblastoma) [6,7]. This fundamental diversity in the pathogenesis of the tumour represents the basic distinction between two different clinical retinoblastoma phenotypes; e.g.…”

Section: Introductionmentioning

confidence: 99%

Retinoblastoma as an Epigenetic Disease: A Proposal

Milardi¹,

Loré²,

Grasso³

2011

JCT

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The aim of the present review is to give 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, as applied to the interpretation of clinical, epidemiological and biological data in retinoblastoma, can not only explain the inconsistencies of the mutational (“two hit”) model, but also open new outstanding scenarios in the fields of diagnosis, treatment and prevention of this eye tumour. This review is both a collection of literature data arguing against the role of the mutational (“two hit”) model in the genesis of retinoblastoma, and a documented evaluation of how the Epigenetic, rather than the genetic model fit the variegated phenotypic expression of the disease. 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 reti-noblastoma in young children. Environmental toxicants, including radiations, wrong diets, and infectious diseases, among others, all play a major role in conditioning the degree of DNA methylation in embryos and foetuses during pregnancy, thus leading to stable, functional alterations of the genome, which, on the other hand, can be also transmit-ted from generation to generation, 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

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“…The different timing and cell type involved by the two mutations determines the different clinical phenotype, with all bilateral and a minority of the unilateral cases being classified as hereditary, and the remaining unilateral cases being included in the sporadic group ( Table 1 ). During the following forty years of epidemiological, clinical, genetic, and biological research in this field, with the discovery of the Rb1 as the prototype tumor suppressor gene, the medical establishment agreed on the pathogenetic “two-hit” theory which was further expanded by Knudson, in many other scientific articles and review papers [ 6 – 24 ]. This generated the widespread conviction that Rb is caused by two mutational events leading to the loss or inactivation of both alleles of the Rb1 gene, as still believed by some authors [ 25 ].…”

Section: Historical Backgroundmentioning

confidence: 99%

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

Milardi

Hadjistilianou

Francesco

et al. 2009

Journal of Cancer Epidemiology

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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.

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A Personal Sixty-Year Tour of Genetics and Medicine

Cited by 14 publications

References 41 publications

Retinoblastoma epidemiology: Does the evidence matter?

Retinoblastoma epidemiology: Does the evidence matter?

Retinoblastoma as an Epigenetic Disease: A Proposal

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

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