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Prb2/P130: a New Candidate for Retinoblastoma Tumor Formation Oncogene (2006) 25, 5333–5340 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW pRb2/p130: a new candidate for retinoblastoma tumor formation G De Falco1,2 and A Giordano1,2 1Department of Human Pathology and Oncology, University of Siena, Siena, Italy and 2Sbarro Institute for Cancer Research and Molecular Medicine, College of Science & Technology Temple University, Philadelphia, PA 19122, USA Retinoblastoma is the most common primary intraocular alterations of tumor suppressor genes and proto- tumor in childhood. Mutations in both the alleles of the oncogenes that mayoccur if genomic integrityis RB1 gene represent the causative agent for the tumor to compromised owing to intrinsic factors or exogenous occur. It is becoming evident that, although these altera- agents. The mechanisms of inactivation of tumor tions represent key events in the genesis of retinoblastoma, suppressor genes and proto-oncogenes are different: they are not sufficient per se for the tumor to develop, and tumor suppressors are inactivated by‘loss of function other additional genetic or epigenetic alterations must mutations’, whereas proto-oncogenes are activated occur. A supportive role in the genesis of retinoblastoma through ‘gain of function mutations’. Tumor suppres- has recently been proposed for the RB1-related gene RB2/ sors are functionallyinactive in cancer cells, thus p130. Additionally, several other genetic alterations invol- determining the loss of control over cell proliferation; ving different chromosomes have been described as relevant on the other hand, proto-oncogenes are constitutively in the tumorigenic process. In this review we will analyse activated, leading to continuous signaling which acts current knowledge about the molecular mechanisms positivelyon cell growth. The different mechanism of involved in retinoblastoma, paying particular attention to inactivation means that when cancer depends on the the mechanisms of inactivation of the biological function of inactivation of a tumor suppressor gene, both the alleles the retinoblastoma family of proteins. of the tumor suppressor gene must be inactivated for the Oncogene (2006) 25, 5333–5340. doi:10.1038/sj.onc.1209614 tumor to occur, even though several lines of evidence indicate that this is not true in the case of haploid Keywords: cell cycle; cancer; RB family; retinoblastoma; insufficiency. Proto-oncogene-driven transformation, on pRb2/p130; tumor suppressors the contrary, requires the mutation of a single copy of the proto-oncogene which then becomes activated, leading cells toward transformation. The first tumor suppressor identified was RB1 (the retinoblastoma susceptibilitygene), mutations of which Introduction are responsible for a childhood retinal malignancy, the retinoblastoma (Friend et al., 1986; Fung et al., 1987; The fact that inherited abnormalities predispose some Lee et al., 1987a, b). The importance of hereditary individuals to cancer was first hypothesized more than factors for the occurrence of this pediatric cancer has one centuryago, but onlyin the past 20 yearshas it been been evident since 1821, when a familial aggregation of possible to identifyseveral genes responsible for retinoblastoma was observed (Kaelin, 1955). Initially, tumorigenesis (Li-Fraumeni syndrome). Cancer may all cases were considered to be inherited diseases, but it be considered a genetic disease, occurring when normal subsequentlybecame clear that there were non-inherited cells progressivelytransform through the acquisition of forms of retinoblastoma (Vogel, 1954). The problem mutations in the genome. When this happens, cells was unraveled in 1971, when Knudson postulated a continue to proliferate independentlyof regulatory model to explain the different origins of hereditaryand influences that control cell growth, whose regulation non-hereditaryretinoblastomas, much earlier than depends on negative and positive growth signals. cloning of the causative gene took place. Negative regulation is exerted bya familyof genes known as tumor suppressors, which regulate cell growth and homeostasis. The proto-oncogenes, whose function Retinoblastoma: the pediatric tumor is to promote cell proliferation, carryout positive regulation of cell growth. It has become increasingly Retinoblastoma is a rare malignant tumor of the eye evident that cancer is a genetic disease, requiring that originates in developing cells of the retina. It has an incidence of 1 in 20 000 live births in all human races Correspondence: Dr A Giordano, Sbarro Institute for Cancer (Suckling et al., 1982), and does not varyaccording to Research and Molecular Medicine, College of Science & Technology Temple University, Biolife Science Bldg. Suite 333, Philadelphia, geographical location or level of industrialization. PA 19122, USA. Diagnosis is possible on the basis of clinical symptoms, E-mail: [email protected] usuallywithin the first 5 yearsof age. Only10% pRb2/p130: a new candidate for retinoblastoma tumor G De Falco and A Giordano 5334 of affected children have a familial historyof retino- model to explain the difference between hereditaryand blastoma, therefore most of the time the tumors are nonhereditaryforms in 1971. This model, referred to as discovered when one or both eyes are already full of the ‘Two-hit hypothesis’, highlights that the phenotypic tumor, giving the pupil a ‘cat’s eye’ appearance due to a difference between these two forms of retinoblastoma white papillaryreflex (leukocoria) which maybe maybe explained bydifferent molecular mechanisms. accompanied bystrabismus. Retinoblastoma occurs in For the tumor to occur inactivation of both the alleles of both hereditaryand nonhereditaryforms: the hereditary the RB1 gene is necessary, but there is a different form accounts for 40% of patients and demonstrates an mechanism for this inactivation. Knudson hypothesized autosomal dominant inheritance; patients have retino- that heritable retinoblastoma tumors depend on a RB1 blastoma in both eyes (bilateral retinoblastoma), often gene mutation, which occurs in germinal cells and can showing more than one focus per eye (bilateral multi- therefore be inherited. Although this first mutation (M1) focal retinoblastoma) and a lifelong predisposition to renders people susceptible to cancer, in not sufficient per cancer throughout the body(Onadim et al., 1992). se for the tumor to develop. In fact, the normal allele About 60% of patients have retinoblastoma in onlyone still provides the required function of RB1 in the eye (unilateral retinoblastoma) and this represents a constitutional cells, in subjects carrying a germline sporadic disease, as there is no familyhistoryfor this RB1 mutation. Tumors will occur onlywhen an cancer. Nonhereditaryretinoblastoma consists of a additional, somatic mutation (M2) arises in retinal cells unifocal retinal tumor and involves no increased risk in the second copyof the gene (the second hit), thus of other cancers. Mutations of both the alleles of inactivating the function of the RB1 gene. In non- the RB1 gene are necessaryfor the disease to occur hereditaryretinoblastoma, both the events are supposed (Friend et al., 1986; Fung et al., 1987; Lee et al., to be somatic (Knudson, 1971; Knudson et al., 1973). 1987a, b). In patients with sporadic unilateral retino- The incidence of nonhereditaryforms depends upon a blastoma, the two RB1 mutations that initiate tumor first somatic mutation in the developing retina, growth development are somatic events and therefore they of the mutant clone, and a subsequent mutation in one cannot be inherited, and none of them are present in cell of that clone. This explains the high incidence of DNA from constitutional cells (Shimuzu et al., 1994; bilateral tumors in patients carrying germline mutations, Lohmann et al., 1997; Klutz et al., 1999). Patients and the younger ages at first appearance of tumor. In affected bybilateral retinoblastoma are heterozygous most hereditaryforms, there are new germinal muta- for an RB1 mutation, which was either inherited or tions and both parents are normal. In the hereditary occurred de novo in parental germline cells or during forms, therefore, M1 occurs in the germinal cells, embryonal development. During early childhood, these whereas M2 occurs in a retinal cell; in nonhereditary patients are predisposed to retinoblastoma because a tumors both M1 and M2, which inactivate both the RB1 mutation in the wild-type allele will lead to biallelic alleles, must arise in the same retinal cell (Figure 1). inactivation of the RB1 gene, therebyinitiating the Almost all kinds of RB1 mutations have been described, development of the tumor focus. In most families with including point mutations, insertions, deletions, trans- retinoblastoma, all members who have inherited a locations (for a review, see Lohmann, 1999). In mutation develop bilateral retinoblastoma. However, addition, epigenetic events such as promoter hyper- in some exceptional families unilateral retinoblastoma is methylation have been described as causative agents for frequent and some mutation carriers remain unaffected (low-penetrance retinoblastoma). In addition to retino- blastoma, carriers of an RB1 mutation also show a high M1 incidence of other tumors that are collectivelyknown as M1 second primaryneoplasms. These include bone and soft tissue sarcomas, malignant melanoma and neoplasms of M1 the brain and meninges (Eng et al., 1993). Diagnosis of M1 M1 patients with bilateral retinoblastoma is made earlier M1 M1 M2 than
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