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and more recent biological and genetic evidences, show that the "two hit" theory represents a rather simplistic, outdated, and unreliable model to explain tumour development and clinical evolution of retinoblastoma.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