Understanding why children with RB mutations specifically develop retinoblastoma will contribute to the understanding of the fundamental principles of cancer. Only a subset of developing retinal cells are at risk for developing cancer when RB is mutant because rod photoreceptor and bipolar cells never normally express RB. Retinoblastomas are observed to arise commonly in the inner nuclear layer, where they can show features attributed to outer nuclear layer cells (photoreceptors). The best-studied function of RB is control of the cell cycle, and the usual tissue consequence of loss of RB is apoptosis. Perhaps the specificity of RB mutation for retinal cancer resides in the dependency of this tissue on programmed cell death to achieve a precise architecture of individual types of interconnecting neurons. The additional mutations that are present in all retinoblastoma, such as the i(6p) marker chromosome, may interrupt signals that normally would induce apoptosis when RB is absent. A combination of loss of cell cycle control and loss of signals that delete extra cells would result in retinoblastoma.
Presented at the “General Motors Cancer Research Foundation Twentieth Annual Scientific Conference: Developmental Biology and Cancer,” June 9–10, 1998, Bethesda, MD.