Retinoblastoma: Revisiting the model prototype of inherited cancer

Abstract

Hereditary retinoblastoma is an autosomal dominant disorder caused by mutations in the RB1 gene. Analysis of this rare condition has helped to elucidate the mechanisms underlying hereditary cancer predisposition in general. As identification of RB1 gene mutations has become a part of clinical management of patients with retinoblastoma, there is now a wealth of data. In this article, we summarize the current knowledge on the relations between the genotype and phenotypic expression. Moreover, detailed analysis of genotype-phenotype relations shows that hereditary retinoblastoma has features of a complex trait.

Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations

“…It is now clear that most mild cases are associated with mutations leading to a reduction in the quantity or quality of cellular pRB activity. Most families showing incomplete penetrance have distinct RB1 mutations such as missense and in-frame mutations that do not result in premature termination codons (Sakai et al 1991;Onadim et al 1992;Lohmann et al 1994;Bremner et al 1997;Otterson et al 1997;Ahmad et al 1999;Lohmann and Gallie 2004). However, the case of incomplete penetrance described in Fig.…”

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…The majority of germline mutations lead to 90% to 95% penetrance, and germline carriers usually develop bilateral or multifocal tumors (6). Nonsense and frameshift mutations in exons 2 to 25 almost always lead to highly penetrant bilateral RB, and they are the most frequent types of mutations found among familial cases (31)(32)(33). The high penetrance is likely due to posttranscriptional nonsensemediated decay, leading to degradation of truncated mRNA transcripts (32).…”

“…Nonsense and frameshift mutations in exons 2 to 25 almost always lead to highly penetrant bilateral RB, and they are the most frequent types of mutations found among familial cases (31)(32)(33). The high penetrance is likely due to posttranscriptional nonsensemediated decay, leading to degradation of truncated mRNA transcripts (32). Lower penetrant mutations with variable expressivity have also been described.…”

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

“…2 Penetrance and expressivity of hereditary RB may depend on the type of inherited mutation, and can vary even within families and among patients with identical mutations. [3][4][5] This indicates a role of modifiers that may affect genome stability to favor the occurrence of somatic mutations, and/or the apoptotic pathway to induce loss or maintenance of the mutated retinoblasts.The p53 pathway, the master control system of these processes, is controlled by a feedback autoregulatory loop in which p53 transcriptionally activates MDM2, that in turn functions as a negative regulator by promoting the proteolytic degradation of p53. Interestingly, this circuit can also target pRB to degradation and in physiological condition controls the cell cycle and apoptosis of the retinal cone precursors, from which the RB cell lineage originates.…”

“…2 Penetrance and expressivity of hereditary RB may depend on the type of inherited mutation, and can vary even within families and among patients with identical mutations. [3][4][5] This indicates a role of modifiers that may affect genome stability to favor the occurrence of somatic mutations, and/or the apoptotic pathway to induce loss or maintenance of the mutated retinoblasts.…”