Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma

Blanquet, Véronique; Turleau, C; Gross-Morand, Marie Sylvie; Sénamaud-Beaufort, Catherine; Doz, François; Besmond, Claude

doi:10.1093/hmg/4.3.383

Cited by 125 publications

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“…Conversion of codon 817 or codon 835 into a premature stop (Liu et al, 1995;Lohmann et al, 1996) and the insertion of two nucleotides resulting in a stop codon following amino acid 825 have been described (Blanquet et al, 1995). The recurrent identification of mutations leading to the loss of C-terminal pRB sequence in retinoblastoma patients, along with the demonstration of loss of functioning in pRB-DELTA exons 24-25, displaying partial loss of C-terminal sequence, provides a strong argument for a disease causing effect of such mutations.…”

Section: Discussionmentioning

confidence: 99%

“…These findings infer a role for pRB in controlling cell homing and invasion, the paracrine management of tissue morphogenesis and the promotion of lineage specific differentiation. Recent work has emphasized the importance of pRBmediated gene activation and gene repression in the prevention of tumor formation, suggesting that these activities may cooperate towards achieving effective tumor suppression (Sellers et al, 1998).The common type of RB1 alteration in patients with retinoblastoma are nonsense mutations predicted to result in the generation of severely truncated pRB forms with complete loss of all functional domains Gallie, 1994;Blanquet et al, 1995;Cowell and Cragg, 1996;Lohmann et al, 1996;Yilmaz et al, 1998;Lohmann, 1999;Alonso et al, 2001;Najera et al, 2001;Houdayer et al, 2004). However, in some instance the alterations have more subtle consequences, including the change, deletion or insertion of single amino acids or the alteration of intronic sequences, which perturbs or prevents correct splicing of the transcript.…”

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A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

et al. 2005

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Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past. © 2004 Wiley-Liss, Inc.KEY WORDS: retinoblastoma; reduced expressivity; penetrance; splicing; RB1; pRB INTRODUCTIONRetinoblastoma, a childhood tumor of the eye, is caused by inactivation in the developing human retina of both alleles of the RB1 tumor suppressor gene (MIM# 180200) (reviewed in DiCiommo et al., 2000). In hereditary retinoblastoma (accounting for roughly 50% of cases) one RB1 allele is mutated in the germ line as either a novel or an inherited mutation. In this instance disease usually presents at an early age, with multiple tumor foci in both eyes, a high incidence of disease recurrence, increased lifetime risk for secondary malignancies and transmission to kindred with a penetrance of greater 95%. In its nonhereditary form mutational inactivation of both RB1 alleles DOI: 10.1002/humu.9305 2 Sánchez-Sánchez et al.arises from somatic events in a single retinal cell. Here disease presentation is far milder disease featuring late onset, single tumor foci in one eye only and absence of recurrence and secondary tumor development. In rare instance hereditary retinoblastoma can present in a form reminiscent to the non-hereditary disease (reduced expressivity), and often in this instance shows reduced penetrance in kindred (low penetrance).The product of the human RB1 gene (p110RB/pRB) is a nuclear phospho-protein composed of 928 amino acids. Through interacting with cellular proteins pRB influences cell proliferation, but also other types of cell behavior (reviewed in Kaelin, 1999;Zheng and Lee, 2001). Most noted is the function of pRB to control gene transcription via E2F (reviewed in Harbour and Dean, 2000;Stevens and La Thangue, 2003). Through association with specific members of this transcription factor family pRB represses genes required for cell cycle progression and proliferation, and by attracting additional chromatin modifyin...

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Section: Discussionmentioning

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A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

et al. 2005

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“…They have been reported to vary from 10-20% in some reports 6 to around 89% in others, 7 using experimental procedures and selection criteria biased toward the inclusion of a large excess of bilateral cases. 7,8 Globally, RB1 gene mutations can be found in no more than 50% (low sensitivity) of all cases, according to some of the most recent reports 9 ; 2. they are commonly found in a great number of non retinoblastoma cancers 9,10 such as osteosarcoma, breast, bladder, lung, head and neck cancer, acute leukaemia, etc.…”

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confidence: 99%

Retinoblastoma epidemiology: Does the evidence matter?

Milardi

Francesco

Leonardo³

et al. 2007

European Journal of Cancer

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AneuploidyTwo hit theory Microsatellite instabilityChromosome instability Epigenetic A B S T R A C T It has been proposed that retinoblastoma is 'caused' by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations.Retinoblastoma remains probably the only cancer in which the rather simplistic 'two hit' mutational model is still considered of value, although cancer is known to be associated with genomic and microsatellite instability, defects of the DNA mismatch repair system, alterations of DNA methylation and hystone acethylation/deacethylation, and aneuploidy.Moreover, as it is shown herein, the predictions made by the 'two hit' model, are not fulfilled by the clinical and epidemiological data reported so far. Moreover, while the role of mutational events in cancer has been largely questioned in the more recent literature, no serious effort has been done to investigate the role of epigenetic alterations and aneuploidy in retinoblastoma.Through the analysis of the specialised literature and a set of original epidemiological and biological data concerning retinoblastoma, the authors illustrate the evidences arguing against the 'two hit' hypothesis and propose that epigenetic factors and aneuploidy play central roles in the disease.

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“…Keywords: retinoblastoma; missense mutation; incomplete penetrance; SSCP Mutational analysis of the RB1 gene has shown that patients with the hereditary form of retinoblastoma (Rb) carry germline mutations within the gene Onadim et al, 1993;Blanquet et al, 1993Blanquet et al, , 1995Lohmann et al, 1994Lohmann et al, , 1996Shimizu et al, 1994). Hereditary cases are de®ned as individuals who have a family history of tumors or individuals without a family history but who have bilateral and/or multifocal tumors usually with an early age of onset.…”

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“…It has now become clear that the majority of mutations identi®ed in individuals with the severe phenotype usually generate premature stop codons (Blanquet et al, 1995;Liu et al, 1995;Cowell et al, 1994;Lohman et al, 1996), either as a result of single base pair mutations or following frame-shifts induced by insertions and deletions. Mutations a ecting splice sites have also been reported in about 30% of cases Liu et al, 1995;Lohmann et al, 1994) which are presumed to result in a non-functional protein.…”

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A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

Cowell

Bia

1998

Oncogene

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We have used single strand conformation polymorphism analysis to study the 27 exons of the RB1 gene in individuals from a family showing`mild' expression of the retinoblastoma phenotype. In this family a ected individuals developed unilateral tumors and, as a result of linkage analysis, una ected mutation carriers were also identi®ed within the pedigree. A single band shift using SSCP was identi®ed in exon 21 which resulted in a missense mutation converting a cys?arg at nucleotide position 28 in the exon. The mutation destroyed an NdeI restriction enzyme site. Analysis of all family members demonstrated that the missense mutation co-segregated with patients with tumors or who, as a result of linkage analysis had been predicted to carry the predisposing mutation. These observations point to another region of the RB1 gene where mutations only modify the function of the gene and raise important questions for genetic counseling in families with these distinctive phenotypes.

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Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma

Cited by 125 publications

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A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

Retinoblastoma epidemiology: Does the evidence matter?

A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

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