The retinoblastoma paradigm revisited.
BACKGROUND
Retinoblastoma (Rb) is the most common primary malignant intraocular tumour in childhood. The "two hit" theory, formulated by Knudson in 1971 to explain the variegated clinical expression of the disease, led to the discovery of the so called tumour suppressor genes and the identification of the Rb1 as the prototype of such genes. Mutations of the Rb1 gene are now commonly believed to be the "cause" retinoblastoma, although epidemiological, clinical, and biological evidences argue against it.


METHODS
The Authors have performed a systematic review of available data concerning clinical and diagnostic aspects of retinoblastoma, including molecular genetics. Meta analysis of literature data has been performed in order to validate some of the predictions made by the two hit theory.


RESULTS
The following theses are discussed in detail: 1) there is no difference in the age at diagnosis between unilateral and bilateral retinoblastoma; 2) the pathogenetic mechanisms underlying familial, hereditary, and sporadic retinoblastoma are different; 3) bilateral retinoblastoma is not necessarily hereditary; 4) The real incidence of the unilateral phenotype within the familial group is disproportionately higher than that predicted by the "two hit"; 5) retinoblastoma is most probably "caused" by the combination of epigenetic factors and aneuploidy.


CONCLUSIONS
Epidemiological, clinical, and more recent biological and genetic evidences, show that the "two hit" theory represents a rather simplistic, outdated, and unreliable model to explain tumour development and clinical evolution of retinoblastoma.
Mastrangelo
Domenico
D
Department of Ophthalmology (Ocular Oncology Unit), University of Siena, Siena, Italy. mastrangelo@unisi.it
De Francesco
Sonia
S
Di Leonardo
Aldo
A
Lentini
Laura
L
Hadjistilianou
Theodora
T
D000367:Age Factors; D006801:Humans; D007223:Infant; D009154:Mutation; D012175:Retinoblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology