Vasoproliferative tumour of the ocular fundus associated with Waardenburg's syndrome.
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Female↗
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Is sunlight an aetiological agent in the genesis of retinoblastoma?
The incidence of unilateral, but not bilateral, retinoblastoma in human populations at different geographical locations increases significantly with ambient erythemal dose of ultraviolet B radiation from sunlight. This supports the hypothesis that sunlight plays a role in retinoblastoma formation.
Adolescent↗
Visual results in children treated for macular retinoblastoma.
PURPOSE: To evaluate the results of patching treatment in children with macular retinoblastoma in one eye. METHODS: Fifteen children affected by macular retinoblastoma received instructions for patching treatment for amblyopia. Data were collected on age at diagnosis of the tumor, presence of unilateral or bilateral disease, area of posterior pole involvement by the scar of the regressed tumor and its relationship to the fovea; and the onset, duration, and compliance of patching. The visual acuities recorded were expressed in logMAR (logarithm minimum angle of resolution) equivalents. RESULTS: Twelve children (80%) had bilateral retinoblastoma with the macular involved in one eye and three children had unilateral macular tumors. The median age at which patching was initiated was 15 months (range 4-36). Compliance to patching was good in 80% of children, with a median duration of 4 h (range 0.5-8) per day, 7 days per week, with total occlusion of the better eye. The median percentage of posterior pole involvement was 34% (range 11-100%). Eighty percent of children had some improvement in their visual acuity, and of the children in whom final logMAR acuity was recorded, 73% had an acuity of 1.0 logMAR or better and 53% an acuity of 0.5 logMAR or better after patching. There was no evidence of association between age of patient, sex, duration of patching, or percentage of posterior pole involvement and the improvement in visual acuity. CONCLUSIONS: In spite of the macular involvement of eyes with retinoblastoma, some visual recovery was achieved in 80% of children. Hence a trial of patching therapy is recommended for all children with involvement of the macula by retinoblastoma.
Amblyopia↗
Vasoproliferative tumours of the retina.
This paper describes three cases of vasoproliferative tumours of the retina including histopathology in one. The clinical presentation, differential diagnosis and treatment modalities are discussed with a brief review of the literature.
Aged↗
Intraocular cysticercosis simulating retinoblastoma in a 5-year-old child.
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Child, Preschool↗
Light-near dissociation of pupil reactions as a presenting feature of von Hippel-Lindau disease.
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Adult↗
The effect of a selective cyclooxygenase-2 (COX-2) inhibitor on the proliferation rate of retinoblastoma cell lines.
PURPOSE: To examine the effect of nepafenac, a selective cyclooxygenase-2 (COX-2) inhibitor, on the proliferation rate of two human retinoblastoma (Rb)cell lines. METHODS: Two human Rb cell lines (WERI-RB and Y79) were cultured. COX-2 expression in these cell lines was verified by immunocytochemical analysis of cytospin sections and Western blotting. An MTT-based proliferation assay was used to compare Rb cell growth with and without amfenac, the active metabolite of nepafenac. The averaged results per condition were recorded. The Student's t-test was used to compare results from the cells cultured with and without amfenac. RESULT: The Y79 cell line showed a higher proliferative rate than the WERI-RB cell line. Both cell lines were negative for COX-2 expression by immunocytochemical analysis; however, both cell lines were positive for COX-2 expression by Western blot. When amfenac was added to both of the cell lines, a statistically significant reduction in proliferation was observed in both cell lines. The two Rb cell lines were positive for COX-2 only in the Western blot, indicating that they probably express low levels of COX-2, which was undetectable by immunocytochemical analysis. CONCLUSION: The selective, anti-COX-2 molecule amfenac inhibited proliferation of both tested Rb cell lines. Further trials should be undertaken to study the effect of selective COX-2 inhibitors on Rb.
Blotting, Western↗
Epipapillary isolated astrocytoma associated with branch retinal artery occlusion in a single eye.
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Astrocytoma↗
A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype.
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 affected individuals developed unilateral tumors and, as a result of linkage analysis, unaffected mutation carriers were also identified within the pedigree. A single band shift using SSCP was identified 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.
Female↗
Tumors of the retinal pigment epithelium metastasize to inguinal lymph nodes and spleen in tyrosinase-related protein 1/SV40 T antigen transgenic mice.
The pigment epithelium of the retina (RPE) is derived from the optic cup and is essential for function and development of the eye. We produced a transgenic mouse line that expresses simian virus (SV40) transforming sequences under control of the 1.4 kb tyrosinase-related protein 1 (TRP-1) promoter, targeting expression of T antigen (Tag) to the RPE. In transgenic embryos, RPE cells proliferated in the anterior part of the eye and near the optic nerve. This resulted in formation of tumors, which were pigmented and of epithelial origin. In 3 months-old mice, pigmented cells were detected in spleen and inguinal lymph nodes. In spleen, tyrosinase, TRP-1 and SV40 Tag were expressed and tyrosinase was enzymatically active. Pigmented regions were positive for an epithelial marker, cytokeratin. Cell lines were established from tumor and metastases and kept in culture for more than 2 months. These were pigmented, and maintained expression of tyrosinase, TRP-1, cytokeratin and SV40 Tag. This demonstrates that RPE tumor cells metastasize to lymph node and spleen. In conclusion, the metastasis from TRP-1/Tag RPE tumors towards spleen and lymph nodes serves as potential tool to investigate biology and metastasis of tumors derived from the pigment epithelium.
Animals↗
The retinoblastoma susceptibility gene product/Sp1 signalling pathway is modulated by Ca2+/calmodulin kinases II and IV activity.
To investigate the possible link between Ca2+ signalling and cell cycle control we analysed Ca2+/calmodulin kinases (CamK) interaction with the retinoblastoma susceptibility gene product/SP1 pathway. CamK II and IV activate c-fos transcription through a short promoter region (-99 to -53) containing the retinoblastoma control element (RCE) and a cAMP response element (CRE) related sequences. Deletion analysis revealed that the RCE is a major CamK responsive element and is sufficient to confer CamK and Ca2+ regulation to a minimal promoter. Direct interactions between SP1 and RCE were confirmed by gel shift experiments. Using transient transfection experiments, we show that CamK-dependent transcription is regulated by the retinoblastoma (Rb) susceptibility gene product and the p107 Rb related protein. However, the stimulatory effects of CamKs and Rb on c-fos are blocked by overexpression of both proteins. These effects appear to be directly mediated by SP1 as shown by the use of a Gal4/SP1 fusion proteins. In conclusion, CamK II and IV, two major Ca2+-dependent intracellular effectors, may represent a molecular link between this second messenger transduction pathway and effectors that control cell cycle progression through Rb/SP1 signalling pathway.
Animals↗
Developmental defects and tumor predisposition in Rb mutant mice.
Targeted gene disruption in the mouse germline permits the introduction of gene mutations similar to those found in inherited human diseases. New advances in gene targeting that enable cell type specific gene disruption in mice further increases the utility of mouse models to study genetic defects as found in cancer. Here we review the phenotypes observed in mice carrying germline mutated copies of the retinoblastoma tumor suppressor gene. We will illustrate how methods that permit tissue-specific Rb inactivation in mice provide new and more versatile tools to gain insight into the etiology of sporadic cancer.
Animals↗
Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB.
Truncating mutations and homozygous deletions in the hSNF5/INI1/BAF47 subunit of human SWI/SNF complexes occur in most malignant rhabdoid tumors and some other malignancies. How loss of hSNF5 contributes to tumorigenesis remains unknown. Because the SWI/SNF subunit BRG1 is required for RB-mediated cell cycle arrest, we hypothesized that hSNF5 deficiency disrupts RB signaling. Here we demonstrate that unlike BRG1, hSNF5 deficient cells retain functional RB since ectopic expression of either p16ink4a or a constitutively active form of RB (PSM-RB) led to cell cycle arrest. To determine how hSNF5 loss might contribute to tumorigenesis, we used a retrovirus to introduce hSNF5 into multiple deficient cell lines. In all cases, re-expression inhibited colony formation and induced cell cycle arrest characterized by a flattened morphology. Flow cytometry revealed that these cells accumulated in G0/G1. Importantly, arrested cells exhibited strong induction of p16ink4a, hypophosphorylated RB, and down-regulation of cyclin A, suggesting that hSNF5 signals upstream of RB to induce growth arrest. Co-expression of SV40 T/t abolished hSNF5-induced G1 arrest and activation of RB. Likewise, HPV-16 E7 was sufficient to partially overcome cell cycle arrest. These results suggest that hSNF5 loss is not equivalent to BRG1/BRM loss in human tumor cell lines. Furthermore, hSNF5-induced cell cycle arrest of deficient cells is mediated in part through activation of p16ink4a expression. These findings provide insight into mechanisms of hSNF5-mediated tumor suppression.
Bromodeoxyuridine↗
Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach.
Human retinoblastoma occurs in two forms (familial and sporadic) both due to biallelic mutation of the RB1/p105 gene even if its loss is insufficient for malignancy. We have recently reported that loss of expression of the retinoblastoma-related protein pRb2/p130 correlates with low apoptotic index, suggesting that RB2/p130 gene could be involved in retinoblastoma. Mutational analysis of RB2/p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of RB2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line by 5-Aza-dC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. Overall, our results highlight a crucial role of epigenetic events in sporadic retinoblastoma, which opens a perspective for new therapeutic approaches.
Azacitidine↗
Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma.
The paediatric eye tumour retinoblastoma is initiated by inactivation of RB1, a tumour suppressor on chromosome 13q. In addition to RB1 loss, many retinoblastomas show other genetic alterations including gains on chromosomes 6p21-pter and 1q31-q32. Recently, the minimal region of gains on chromosome 6 was narrowed to band p22. We examined genomic gains and expression changes in primary retinoblastomas to identify potential target genes in 6p22. Quantitative multiplex PCR detected copy numbers > or = 3 in 25 (33%) tumours and no gains in 31 of 76 (40%) tumours. The remaining 20 (26%) samples showed gains only at some loci, most often including E2F3 and DEK in 6p22.3. Analysis of RNA from 21 primary retinoblastomas showed that expression levels of these and some other genes in 6p22 correspond to DNA gains. However, KIF 13A, a reported candidate oncogene on 6p, was expressed at low levels or absent. Clinical manifestation of tumours with gains at all 6p22 loci was distinct in that distribution of age at diagnosis was markedly shifted to older age compared to tumours with no or partial gains. In summary, our results suggest that DEK and E2F3 are potential targets of 6p gains in retinoblastoma.
Base Sequence↗
pRb2/p130: a new candidate for retinoblastoma tumor formation.
Retinoblastoma is the most common primary intraocular tumor in childhood. Mutations in both the alleles of the RB1 gene represent the causative agent for the tumor to occur. It is becoming evident that, although these alterations represent key events in the genesis of retinoblastoma, they are not sufficient per se for the tumor to develop, and other additional genetic or epigenetic alterations must occur. A supportive role in the genesis of retinoblastoma has recently been proposed for the RB1-related gene RB2/p130. Additionally, several other genetic alterations involving different chromosomes have been described as relevant in the tumorigenic process. In this review we will analyse current knowledge about the molecular mechanisms involved in retinoblastoma, paying particular attention to the mechanisms of inactivation of the biological function of the retinoblastoma family of proteins.
Cell Cycle↗
Anaesthesia for retinoblastoma screening--a dilemma.
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Anesthesia, General↗
Multiple acral fibromas in a patient with familial retinoblastoma: a cutaneous marker of tumour-suppressor gene germline mutation?
We report a 40-year-old patient with familial retinoblastoma also affecting his elder son, who developed multiple fibromas on the periungual or subungual areas of all the fingers. Molecular analysis disclosed a loss of heterozygosity for the RB1 gene in the larger tumour, with disappearance of the normal allele and persistence of the mutated allele only. The similarity of this observation with distal fibrous tumours encountered in other diseases with germline mutations of tumour-suppressor genes such as neurofibromatosis type 1, tuberous sclerosis and multiple endocrine neoplasia type 1 led to the hypothesis that multiple acral benign tumours with a fibrous component might be a cutaneous marker of tumour suppressor gene germline mutation with low sensitivity but high specificity.
Adult↗