1. Mutations in the retinoblastoma tumor-suppressor gene (RB1) contribute to inherited and sporadic cancers. The figure indicates that cell context affects the contribution of RB1 mutations to cancer development. In individuals carrying a germ line mutation in one RB1 allele, somatic inactivation of the remaining normal RB1 allele is an early and rate-limiting event in retinoblastoma formation. Sporadic forms of retinoblastoma are also dependent on inactivation of both RB1 alleles. Because somatic inactivation of both RB1 alleles must occur in a single developing retinoblast before tumor formation can ensue, retinoblastoma is a rare disease in those who do not carry a germ line RB1 mutation. A rather paradoxical finding is that those who carry a germ line RB1 mutation are not highly predisposed to other cancer types, such as lung cancer, despite RB1 mutations being frequently observed in sporadic forms of lung cancer (e.g., small cell lung carcinoma). These observations imply that RB1 mutations are likely contributors to tumor progression rather than to tumor initiation in most cancer types, other than retinoblastoma and, perhaps, osteosarcoma. Possible explanations are that inactivation of both RB1 alleles prior to the acquisition of other mutations in oncogenes or tumor-suppressor genes is not associated with any growth advantage, and perhaps RB1 inactivation may even be associated with induction of apoptosis. (Figure modified with permission from Fig. 1 of Haber DA, Fearon ER: The promise of cancer genetics. Lancet 351 (suppl II):1, 1998.)
Source: Controls on Cell Cycle, The Online Metabolic and Molecular Bases of Inherited Disease
Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: Accessed: October 11, 2017
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