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

Abstract

Retinoblastoma (RB) is an important ocular malignancy of childhood. It has been commonly accepted for some time that knockout of the two alleles of the RB1 gene is the principal molecular target associated with the occurrence of RB. In this article, we examine the validity of the two-hit theory for RB by comparing the fit of a stochastic model with two or more mutational stages. Unlike many such models, our model assumes a fully stochastic stem cell compartment, which is crucial to its behavior. Models are fitted to a population-based dataset comprising 1,553 cases of RB for the period 1962-2000 in Great Britain (England, Scotland and Wales). The population incidence of RB is best described by a fully stochastic model with two stages, although models with a deterministic stem cell compartment yield equivalent fit; models with three or more stages fit much less well. The results strongly suggest that knockout of the two alleles of the RB1 gene is necessary and may be largely sufficient for the development of RB, in support of Knudson's two-hit hypothesis.

Figure 1

The observed and predicted age-specific incidences (with 95% CI) of bilateral and unilateral RB cases in the general population from 1962 to 2000, from the optimal model with bilateral 1-stage + unilateral 2-stage models, no latency, reduced stochastic delay model with separate adjustment for RB1 heterozygous and RB1 wildtype homozygous unilateral cases, G₂₀+=G₁₀+, D₂₀+=D₁₀+, with population prevalence of RB1 heterozygotes constrained to be 2.0 × 10⁻⁵ (Tables 3, A2).

Figure 2

The number of susceptible retinal cells predicted by the optimal model with bilateral 1-stage + unilateral 2-stage models, no latency, reduced stochastic delay model with separate adjustment for RB1 heterozygous and RB1 wildtype homozygous unilateral cases, G₂₀+=G₁₀+, D₂₀+=D₁₀+, with population prevalence of RB1 heterozygotes constrained to be 2.0 × 10⁻⁵ (Tables 3, A2).