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Analysis of retinoblastoma age incidence data using a fully stochastic cancer model

Mark P Little1, Ruth A Kleinerman, Charles A Stiller

  • 1Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, DHHS, NIH, Bethesda, MD 20852-7238, USA. mark.little@nih.gov

International Journal of Cancer
|March 10, 2011
PubMed

Insights

Knudson's two-hit hypothesis is supported by new research on childhood retinoblastoma (RB). The study indicates that inactivating both RB1 gene alleles is necessary and likely sufficient for RB development.

Area of Science:

  • Ophthalmology
  • Genetics
  • Cancer Biology

Background:

  • Retinoblastoma (RB) is a significant childhood eye cancer.
  • The prevailing theory suggests RB arises from the inactivation of both RB1 gene alleles.

Purpose of the Study:

  • To rigorously test Knudson's two-hit hypothesis for retinoblastoma.
  • To evaluate stochastic models of cancer development against population data.

Main Methods:

  • A stochastic mathematical model with varying mutational stages was developed.
  • The model was fitted to a large dataset of 1,553 British retinoblastoma cases (1962-2000).
  • Model fit was assessed using a fully stochastic stem cell compartment.

Main Results:

  • A two-stage stochastic model provided the best fit for the population incidence of retinoblastoma.
  • Models with three or more stages demonstrated a significantly poorer fit.
  • A deterministic stem cell compartment model showed equivalent fit to the two-stage stochastic model.

Conclusions:

  • The findings strongly support that the knockout of both RB1 gene alleles is necessary and largely sufficient for retinoblastoma development.
  • The study validates the core principles of Knudson's two-hit hypothesis in the context of retinoblastoma.
  • A two-stage mutational process, likely involving RB1 inactivation, is the most parsimonious explanation for RB incidence.

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