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© Borgis - Postępy Nauk Medycznych 11/2010, s. 854-859
*Stanisław Zajączek
Retinoblastoma
Siatkówczak
International Hereditary Cancer Center, Genetics and Pathology Unit, Cytogenetics Unit, Department of Pathology, Pomeranian Medical University, Szczecin
Head of the Genetics and Pathology Unit: prof. dr hab. med. Jan Lubiński
Head of the Cytogenetics Unit: prof. dr hab. Stanisław Zajączek
Streszczenie
Siatkówczak jest modelowym nowotworem o podłożu genetycznym. Warunkowany jest dominującymi mutacjami jednej kopii genu RB1, które mogą mieć charakter somatyczny (S. sporadyczny, zwykle jednostronny) lub konstytucyjny (często obustronny i/lub wieloogniskowy). Do powstania guza konieczne jest jeszcze „drugie trafienie”, które ma już charakter mutacji somatycznej. Unieczynnienie obu kopii genu odblokowuje cykl komorkowy w fazie G1-S i inicjuje nowotwór. Gen RB1 składa się z 27 eksonów, mutacje nie wykazują preferencji lokalizacyjnych typu hot spot (co utrudnia diagnostykę), jednak ostatnio opisano pewne preferencje lokalizacyjne i etniczne w charakterystyce mutacji. Omówiono uwarunkowania genetyczne i charakterystykę rodowodowo-kliniczną siatkówczaka. Podano zasady diagnostyki genetycznej siatkówczaka a także zasady opieki nad rodzinami obciążonymi zmutowanym genem. Z uwagi na występowanie nosicieli mutacji konstytucyjnych również w grupie pacjentów z guzami jednostronnymi sporadycznymi, wszyscy chorzy z siatkówczakiem jak i ich rodzeństwo powinni być poddawani badaniom profilaktycznym do chwili potwierdzenia/wykluczenia mutacji. Nosicielstwo mutacji konstytucyjnej powoduje także w późniejszym życiu pacjenta podwyższone ryzyko innych pierwotnych nowotworów, zwłaszcza mięsaków.
Summary
Retinoblastoma genetics is a model system for gaining knowledge on the basic features of all hereditary cancers. A tumor is caused by inactivating mutations in both copies of the RB1 gene. They are transmitted as "one hit” in a dominant manner, but an inactivation of the second gene copy is needed for initiation. In hereditary form (frequently bilateral/multifocal) the first "hit” is constitutional and inherited but a second hit is a somatic mutation. In sporadic form (mostly unilateral and unifocal) both "hits” are somatic mutations. Inactivation of both RB1 gene copies abolishes the cell cycle block between G1 and S phase initializing carcinogenesis. The RB1 gene consists of 27 exons, mutations do not exhibit hot spots, but some spatial and ethnic regularities were detected in recent years. Hereditary determination, clinical value of pedigree and molecular analysis of the RB1 gene are described, as well as basic rules of familial care. Due to the detection of constitutional mutations in some sporadic/unilateral cases, carrier status in some patients with non-familial, unilateral tumors ( de novo and germ-line or low penetrant mutations) prophylactic investigations of all first degree relatives must be performed, until their molecular verification is done. Since a patient with a sporadic, unilateral tumor might be a constitutive mutation carrier, all patients with retinoblastoma and their siblings should be tested until the mutation is confirmed or excluded.
Patients with constitutional mutations also have a higher risk of secondary primary tumors, particularly sarcomas.
Retinoblastoma (Rb) plays a significant role among tumors. It is the first neoplasm with the hereditary etiology that has been demonstrated. It helped in developing the "two-hits” hypothesis and the suppressor gene idea (4, 5, 15, 17).
The incidence of Rb is 1 in 25,000 of live-born infants. Despite its rarity, Rb is the most common intraocular neoplasm in children. In the majority of cases it is diagnosed before the age of 5 years. Rb scarcely occurs in adults. 60% of cases of Rb show a true sporadic character. These are the results of somatic mutations occurring in the retinal cells. The remaining 40% of patients are children with constitutive mutations. Among them 10-15% are familial cases and the remaining 25-30% are new in the family as the result of a de novo germinal constitutive mutation. The penetrance of the constitutive mutation reaches 90%. For the onset of neoplasm the inactivation of protein pRB is needed. It occurs after the function of both alleles has been lost or inactivated (17).
The probability of the appearance of two consecutive somatic mutations in the RB1gene in the same retina cell, as it happens in the sporadic form of Rb, is directly proportional to the duration of cell life. It explains the late onset and usually unilateral and unifocal development of such forms of Rb in comparison with Rb caused by constitutive mutation (fig. 1). According to the "two-hits” hypothesis the development of the tumors in patients with a constitutive mutation requires only a next simple somatic mutation in retina cell. This is more likely to happen earlier, compare to two accidental sporadic mutation, thus the average age of patients with hereditary form of Rb is lower. Furthermore, the second somatic mutation in a carrier of the constitutive mutation may appear in a greater number of cells, hence the multifocal and bilateral development of such tumors is common (4, 17).
Fig. 1. Typical pedigree of a sporadic retinoblastoma without a constitutive mutation.
Legend for pedigrees presented in figures 1-4:
-/- a constitutive mutation excluded
+/- a constitutive mutation present in one allele
3 2/12 the age of diagnosis in years and months
(12) current age in years
Bilateral and unilateral multifocal cases of Rb are usually associated with the presence of a constitutive mutation which is either transmitted from ancestors or acquired de novo. In the majority of cases, they appear before the age of 3 years (fig. 2, 3). Constitutive mutations may also arise de novo in germ cells (fig. 2). However, tumors associated with such mutations have a sporadic family pedigree, they show different symptoms and an earlier onset, which make them more similar to familial cases. Certain patients, (20% in our own studies) despite the unilaterality of the Rb at the moment of diagnosis, carry a constitutive mutation. Compared to other unilateral cases of Rb, tumors in such patients occur earlier and are multifocal. What more, those patients are at a high risk of a new primary tumor growth in the same or other eye (10, 13, 14, 16, 17).
Fig. 2. Typical pedigree of a hereditary retinoblastoma as a consequence of a constitutive mutation de novo.
Fig. 3. Typical pedigree of hereditary retinoblastoma as a consequence of a de novo constitutive mutation ? (II-1) with complete (III-1) and possibly incomplete expression and penetrance (III-2).
RETINOBLASTOMA GENE AND PROTEIN
The RB1gene is of medium size (200 kb). It is located in the 13q14 chromosome region, and comprises a promoter and 27 exons. There is a single RNA transcript of 4.8 kb size known. Therefore, the alternative RNA splicing of the RB1gene presumably does not take place.
The RB1gene encodes a p105RB1 protein, which belongs to the pocket protein family and is a nuclear phosphoprotein of 105-110 kDa size. It participates in complex regulatory pathways, which control the pass from G1 into S phase in the cell cycle. Therefore, it is one of the key proliferation regulators. This process concerns all cells in the organism and the gene shows a high evolutionary conservation. The protein affects the functions of many other genes by inactivation (sequestration) of one of the main transcription regulators – E2F factor. This is performed by E2F binding to the pRB1 pocket domain. It disables the transactivation of dependent genes by E2F. The result is that cells remain in the G0 phase. Only the pRB1 protein with the hypophosphorylation on its serine residues has the ability for binding E2F; the hyperphosphorylation of the protein releases the transcription factor and enables the passing from G1 phase to S phase and the progression of the cell cycle. Some proteins of oncogenic viruses such as the E7 protein of the papilloma virus, the E1A protein of adenovirus, T-antigen of the SV40 virus and others bind competitively to the pocket domain of the pRB1 protein. This phenomenon allows for associating the virus ontogenesis processes with the appearance of genetically determined neoplasms. The pocket domain of pRB1 protein may bind many other proteins containing the -Leu-x-Cys-x-Glu- chain (4, 6, 7, 15, 26). Sequence mutations found in patients with Rb diagnosed are predominantly located in the protein pocket domain and its vicinity. They can affect the affinity for transcription factors. When such a blocking is not complete, mutations are of a low penetrance (see below).
The universal regulatory character of the pRB1 protein can explain its mutation involvement in arising from many others tumors, such as osteosarcoma, bladder cancer, small cell lung cancer etc., co-occurring in families with retinoblastoma history (1).
The activity of the RB1gene is regulated by the promoter and the associated transcription regulators. Few known promoter mutations downgrade this regulation and show clinical features of low penetrance (see below). One of them and the first de novo recognized mutation was identified in author's center (28, 29). Regular cell functioning requires the presence of only one normal allele. Constitutive mutation carriers, apart from having a predisposition to develop Rb, do not differ from healthy individuals having two normal alleles.
TIME COURSE AND CLINICAL PATTERN
The peak incidence of retinoblastoma is at the age of about 42 months. More than 90% of cases are diagnosed before the age of 5 years. There are known cases where the tumor was diagnosed immediately after birth. Early symptoms indicating Rb are squinting, red eye and inflammation of the eyeball. However, the tumor is usually diagnosed by symptoms appearing later on. They are exophthalmos and a "cat's eye” noticed by parents – white pupil, which comes from the caseous surface of the tumor itself. Treatment at an early stage frequently allows preservation of the affected eyeball even with the vision field worsened. The diagnosis at a later stage, unfortunately the most common situation, when the "cat's eye” sign is present, usually requires the removal of the eyeball. It is often associated with radiotherapy and chemotherapy (6, 17).
Metastases of retinoblastoma are rare. The tumor spreads usually per continuitatem, mainly into adjacent tissues via the optic nerve. The prognosis depends mainly on the quality of diagnostics and health care. In developed countries with good medical care standards the mortality rate hardly exceeds 8% of the cases, and eyeball removal is necessary in about 10% of cases. In developing countries the mortality rate can reach 100%.
MOLECULAR BACKGROUND OF THE HEREDITARY RETINOBLASTOMA
Currently RB1gene mutations have been noted in databases in ~1000 patients with constitutive retinoblastoma (8, 14, 25). They are classified with all generally known mutation categories: different types of point mutations, translocations, insertions, and deletions. Recently a relatively great occurrence of deletions among all mutations has been found. In previous years they were neglected. Particular classes of RB1gene alterations are point mutations in exonic and intronic sequences, mutations generating aberrant splicing, point mutations of promoter, and modifications of their methylation status (epigenetic changes) without alterations of sequence per se.
The majority of hereditary mutations, particularly in bilateral cases, are nonsenses and frameshifts. They generate premature stop codons and are localized in exons 1-25. No mutation has been identified until now in the last two exons 26 and 27. Although, they are potentially mutation prone sites due to two potential hot spots, CGA.

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Piśmiennictwo
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otrzymano: 2010-10-01
zaakceptowano do druku: 2010-10-29

Adres do korespondencji:
*Stanisław Zajączek
Międzynarodowe Centrum Nowotworów Dziedzicznych Zakład Genetyki i Patomorfologii i Samodzielna Pracownia Cytogenetyki Katedry Patologii, Pomorski Uniwersytet Medyczny
ul. Połabska 4, 70-115 Szczecin
tel.: (91) 466-15-32
e-mail: blue1945@o2.pl

Postępy Nauk Medycznych 11/2010
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