ABSTRACT
Retinoblastoma is the most common ocular cancer of children. Several years ago, Knudson noted that the incidence of retinoblastoma followed a statistical pattern of inheritance suggesting the acquisition of two mutations [1]. He proposed the ‘‘twohit’’ mutation hypothesis as a mechanism of at least initially developing this form of cancer. Comings elaborated on this model shortly thereafter and proposed that the two mutations were actually affecting the two alleles of the same gene [2]. This theory lead to the concept of tumor suppressor proteins and ultimately to the cloning of the retinoblastoma susceptibility gene (Rb1) and the characterization of its protein product (pRB) [3-5]. Mutations in both alleles of the Rb1 gene that lead to protein dysfunction, improper expression, or loss of heterozygosity have been identified in all human retinoblastomas to date.
