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1.
Ophthalmologe ; 117(4): 389-402, 2020 Apr.
Article in German | MEDLINE | ID: mdl-32206913

ABSTRACT

Retinoblastomas represent 6% of all malignant tumors in children under 5 years old, which untreated lead to blindness in the affected eye and death due to metastases. The main symptoms are leukocoria and strabismus, which if possible, always necessitate a clarification within 1 week for exclusion of a retinoblastoma. The most frequent differential diagnoses are Coats' disease and persistent fetal vasculature (PFV) as well as other intraocular tumors, in particular astrocytomas. Systemic chemotherapy, if necessary in combination with laser hyperthermia, local chemotherapy and brachytherapy are the most important methods for eye-preserving treatment. Advanced cases mostly necessitate enucleation.


Subject(s)
Brachytherapy , Persistent Hyperplastic Primary Vitreous , Retinal Neoplasms , Retinoblastoma , Child, Preschool , Eye Enucleation , Humans , Infant , Retinal Telangiectasis
2.
Klin Monbl Augenheilkd ; 230(7): 686-91, 2013 Jul.
Article in German | MEDLINE | ID: mdl-23877823

ABSTRACT

Uveal melanoma is the most common primary intraocular tumour in Caucasians. There are approximately 500 new cases of uveal melanoma in Germany per year and the incidence rate peaks at the age of 70 years. Half of all uveal melanoma patients develop metastatic disease, which can be observed even many years after successful treatment of the primary tumour. In most cases the liver is the location of first manifestation. Based on the chromosome 3 status uveal melanomas can be divided into two major classes that differ in their metastatic potential. Tumours with a high risk to metastasise usually show monosomy 3, whereas tumours showing disomy 3 rarely metastasise. If a patient wishes to know about his individual risk, prognostic testing of the primary tumour tissue can be performed after obtaining tumour material via transscleral or transretinal biopsy, or by enucleation. To date results of prognostic testing do not influence therapeutic strategies. Recently, major key genes involved in uveal melanoma development, GNAQ, GNA11, BAP1, SF3B1 and EIF1AX, have been identified. Mutation profiling, in addition to chromosomal 3 analysis, will further refine the classification or subclassification of uveal melanomas and will hopefully influence diagnostic or therapeutic concepts. Hereditary mutations in tumour suppressor gene BAP1 are associated with an increased risk for different tumour entities. Detection of germ line mutations in this tumour suppressor gene should implicate further general screening examinations of the patient to be able to detect these tumour entities. Moreover relatives of these patients should be offered a screening for BAP1 mutation.


Subject(s)
Genetic Markers/genetics , Genetic Testing/methods , Melanoma/genetics , Melanoma/secondary , Molecular Biology/methods , Uveal Neoplasms/diagnosis , Uveal Neoplasms/genetics , Genetic Predisposition to Disease/genetics , Humans , Melanoma/diagnosis
3.
Klin Monbl Augenheilkd ; 230(3): 232-42, 2013 Mar.
Article in German | MEDLINE | ID: mdl-23508752

ABSTRACT

There are approximately 40 new cases of retinoblastoma in Germany per year. Children in whom the tumour is detected when still intraocular have an excellent overall survival rate (> 95%). However, the prognosis of metastasised retinoblastoma remains poor. About 40% of retinoblastoma patients have tumours in both eyes. For these children in particular it is important to save the eye and visual function as much as possible. There are several options for conservative treatment of localised retinoblastoma including laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. In recent years, systemic chemotherapy has become the established standard for primary treatment of intraocular retinoblastoma. In case series, intra-arterial, intravitreal and periocular applications of chemotherapy were also shown to be effective in treating intraocular retinoblastoma. Genetic testing is an integral part of the routine diagnostics of all patients. Mutation analysis of tumour material is invaluable for identification of somatic mutations including mutational mosaicism. Genetic testing also identifies children with heritable retinoblastoma, which represent 50% of cases. These children also have a predisposition for the development of tumours outside of the eye (second primary neoplasm). To adequately address these and other late effects in survivors of retinoblastoma, a multidisciplinary approach is needed that optimises therapy and long-term follow-up. Upcoming multicentre clinical trials will evaluate treatment concepts for localised and metastasised retinoblastoma to improve survival rates and quality of life of children with retinoblastoma. This article was translated and modified and was primarily published in Klin Padiatr 2012; 224: 339-347.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Eye Enucleation , Postoperative Complications/prevention & control , Retinal Neoplasms/diagnosis , Retinal Neoplasms/therapy , Retinoblastoma/diagnosis , Retinoblastoma/therapy , Visual Acuity/drug effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemoradiotherapy, Adjuvant , Child , Disease Progression , Drug Administration Routes , Genetic Predisposition to Disease , Humans , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Retinal Neoplasms/genetics , Retinal Neoplasms/pathology , Retinoblastoma/genetics , Retinoblastoma/pathology , Treatment Outcome
4.
Klin Padiatr ; 224(6): 339-47, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23143761

ABSTRACT

Retinoblastoma affects approximately 40 children in Germany per year. Most children are diagnosed early with localized intraocular disease, and the overall survival rate exceeds 95%. However, the prognosis of metastasized retinoblastoma remains poor. In 40% of the patients, retinoblastoma occurs bilaterally and, especially for these children, the salvage of the eye and visual function is of major importance. The variety of conservative treatment options for localized retinoblastoma includes laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. While systemic chemotherapy has nearly completely replaced external beam radiotherapy in the primary treatment of intraocular retinoblastoma, intra-arterial, intravitreal and periocular application of chemotherapy was also shown to be effective in treating intraocular retinoblastoma in case series. Genetic testing is an integral part of the routine diagnostics of all patients. Available tumor material should be analyzed to detect mutational mosaicism, that affects >10% of children with unilateral retinoblastoma. Genetic testing also identifies children with heritable (50% of patients) retinoblastoma. These children have a genetic predisposition for second malignancies. For this reason, late effects are an increasing concern and the care of patients with retinoblastoma requires a multidisciplinary approach to tailor therapy and long-term follow-up. Multicenter clinical trials are being developed to evaluate evidence-based treatment concepts for localized and metastasized retinoblastoma to improve survival rates and quality of life of children with retinoblastoma.


Subject(s)
Retinal Neoplasms/diagnosis , Retinal Neoplasms/therapy , Retinoblastoma/diagnosis , Retinoblastoma/therapy , Vision Disorders/diagnosis , Vision Disorders/prevention & control , Vision Disorders/therapy , Child , Combined Modality Therapy , Cooperative Behavior , Disease Progression , Early Diagnosis , Genes, Retinoblastoma/genetics , Genetic Testing , Humans , Interdisciplinary Communication , Neoplasm Staging , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/mortality , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/therapy , Prognosis , Retinal Neoplasms/genetics , Retinal Neoplasms/mortality , Retinal Neoplasms/pathology , Retinoblastoma/genetics , Retinoblastoma/mortality , Retinoblastoma/pathology , Survival Rate , Vision Disorders/mortality , Vision Disorders/pathology
5.
Mol Syndromol ; 2(2): 53-59, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22712005

ABSTRACT

Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1.

6.
Br J Cancer ; 106(6): 1171-6, 2012 Mar 13.
Article in English | MEDLINE | ID: mdl-22353812

ABSTRACT

BACKGROUND: In uveal melanoma (UM), the most frequent primary intraocular tumour in adults, loss of one entire chromosome 3 (monosomy 3 (M3)) is observed in ~50% of tumours and is significantly associated with metastatic disease. The strong association of metastatic disease with M3 offers the opportunity for molecular prognostic testing of UM patients. METHODS: To re-evaluate M3 as prognostic marker in our clinical and laboratory setting and to determine the metastatic potential of rare tumours with partial M3, we performed a comprehensive study on 374 UM patients treated by enucleation in our clinic within 10 consecutive years, starting in 1998. Genotyping of all tumours was performed by microsatellite analysis. RESULTS: Median follow-up time was 5.2 years. The disease-specific mortality rates (death by UM metastases) for tumours with disomy 3 (D3) and M3 were 13.2% and 75.1%, respectively. The disease-specific survival was worse when M3 was observed together with chromosome 8 alterations (P=0.020). Death of UM metastases was also observed in 12 patients (9%) with D3 tumours. The metastasising D3 tumours showed a larger basal tumour diameter (P=0.007), and were more frequently of mixed or epitheloid cell type (P<0.0001) than D3 tumours that did not metastasise. Mortality rate of tumours showing partial M3 (8.3%) was as low as that for tumours with D3. CONCLUSION: This shows that large tumours with disomy 3 have an increased risk to develop metastases. On the basis of these results, our clinic offers routine prognostic testing of UM patients by chromosome 3 typing.


Subject(s)
Biomarkers, Tumor/genetics , Chromosomes, Human, Pair 3 , Melanoma/diagnosis , Microsatellite Repeats , Monosomy , Uveal Neoplasms/diagnosis , Aged , Aged, 80 and over , Chromosomes, Human, Pair 8 , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Melanoma/genetics , Melanoma/mortality , Melanoma/secondary , Middle Aged , Prognosis , Proportional Hazards Models , Tumor Burden , Uveal Neoplasms/genetics , Uveal Neoplasms/mortality , Uveal Neoplasms/pathology
7.
Klin Monbl Augenheilkd ; 228(7): 593-8, 2011 Jul.
Article in German | MEDLINE | ID: mdl-21739401

ABSTRACT

Retinoblastomas are the most frequent primary malignant intraocular tumours worldwide. Conventional and new treatment modalities have significantly improved the chance for survival and preservation of vision. The armamentarium of treatment modalities has been broadened recently by new techniques like intraarterial chemotherapy, which still has to be considered as experimental since long-term follow-up results are not yet available. The excellent prognosis for retinoblastomas in countries with a well developed health system is contrasted by the miserable prognosis for retinoblastomas in developing countries, which must be changed by a joint effort of all centres.


Subject(s)
Genetic Therapy/trends , Molecular Biology/trends , Ophthalmology/trends , Retinal Neoplasms/genetics , Retinal Neoplasms/therapy , Retinoblastoma/genetics , Retinoblastoma/therapy , Forecasting , Germany , Humans
8.
Biorheology ; 47(3-4): 205-24, 2010.
Article in English | MEDLINE | ID: mdl-21084745

ABSTRACT

The focus of this work is on a comparative rheological characterization of sodium hyaluronate (NaHA) samples from fermentative production (NaHA-1, Mw = 1.7 × 106 g/mol) and from rooster comb (NaHA-2, Mw = 4.6 × 106 g/mol) with synovial fluid (SF) taken post mortem from different patients above 60 years. Steady state shear flow and uniaxial extension experiments were carried out for different concentrations of NaHA in 0.01 M phosphate-buffered saline (PBS) and on several SF samples.The synovial fluid of older patients was found to have a viscoelasticity comparable to that of younger patients investigated in earlier studies. Comparison of steady state shear experiments revealed a comparable progression for the viscosity curves of NaHA-2 and SF. This behavior was also observed in extensional flow, where comparable results for NaHA-2 and different SF samples were obtained.


Subject(s)
Hyaluronic Acid/metabolism , Rheology , Shear Strength/physiology , Synovial Fluid/physiology , Aged , Aged, 80 and over , Centrifugation , Female , Humans , Male , Middle Aged , Models, Biological , Solutions , Time Factors , Viscosity
9.
Zentralbl Neurochir ; 69(4): 194-9, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18666063

ABSTRACT

The authors present a case of 44-year-old Caucasian female diagnosed with meningothelial meningioma 40 years after radiotherapy for sporadic unilateral retinoblastoma. The genetic analysis of DNA from the meningioma revealed no oncogenic mutation in the RB1 gene. The analysis of meningioma cells by flow cytometry revealed the following immunophenotype: vimentin++ CD56+ GFAP- EGFR-. Intermediate intensities of Her-2/neu and Pgp expression were detected in a small percentage of tumour cells. Data suggest that the tumour was most likely induced by radiotherapy and did not arise as a second tumour as there was no hereditary predisposition to retinoblastoma.


Subject(s)
Meningioma/etiology , Meningioma/pathology , Radiotherapy/adverse effects , Retinal Neoplasms/genetics , Retinal Neoplasms/radiotherapy , Retinoblastoma/genetics , Retinoblastoma/radiotherapy , Adult , Biomarkers, Tumor , DNA, Neoplasm/genetics , Female , Flow Cytometry , Humans , Immunohistochemistry , Meningioma/genetics , Mutation , Nerve Tissue Proteins/genetics , Phenotype , Tomography, X-Ray Computed
10.
Ophthalmologe ; 103(1): 59-76; quiz 77-8, 2006 Jan.
Article in German | MEDLINE | ID: mdl-16382314

ABSTRACT

Retinoblastomas are the most frequent intraocular tumors in childhood. Untreated, the tumor is almost always fatal. Using a multidisciplinary approach combining the efforts of ophthalmologists, radiation oncologists, pediatric oncologists and geneticists a survival rate of more than 95% can be achieved. Molecular genetic research on the origin of retinoblastomas has substantially helped in our understanding of the origin of malignant tumors in general, as well as to the key role of the Rb-1 gene as a tumor suppressor.


Subject(s)
Eye Neoplasms/diagnosis , Eye Neoplasms/therapy , Retinoblastoma/diagnosis , Retinoblastoma/therapy , Diagnosis, Differential , Eye Neoplasms/genetics , Eye Neoplasms/mortality , Humans , Practice Guidelines as Topic , Practice Patterns, Physicians' , Retinoblastoma/genetics , Retinoblastoma/mortality
11.
Hum Mutat ; 26(5): 437-45, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16127685

ABSTRACT

Quantitative multiplex PCR and genomic real-time PCR were used to complete an RB1 mutation analysis in 57 of 433 and 72 of 262 patients with hereditary and isolated unilateral retinoblastoma, respectively. These patients were selected because in previous analyses, which focused mainly on the identification of point mutations, no RB1 mutation was found. We identified gross deletions and insertions in peripheral blood DNA from 26 of 57 patients (46%) with hereditary retinoblastoma, and in six of 72 patients (8.3%) with isolated unilateral disease. In addition, we identified 32 somatic mutations in tumor DNA from 31 of 72 patients (43%) with isolated unilateral retinoblastoma. Together with our previous results, we found that gross RB1 alterations were present in the peripheral blood DNA from 65 of 433 (15%) and 17 of 262 (6.5%) patients with bilateral or familial and isolated unilateral retinoblastoma, respectively. Including reported gross deletions, an analysis of the frequency of breakpoints per intron length shows higher densities in introns 13, 16, 23, and 24. Genotype-phenotype analyses showed that on the whole, carriers of gross deletions develop fewer retinoblastomas compared to patients who are heterozygous for other types of RB1 null mutations. Specifically, carriers of cytogenetic and submicroscopic whole gene deletions often have unilateral tumors only. By contrast, almost all patients with gross deletions with one breakpoint in RB1 have bilateral retinoblastoma.


Subject(s)
Genes, Retinoblastoma , Mutation , Retinoblastoma/genetics , DNA Mutational Analysis , Gene Deletion , Gene Duplication , Genotype , Humans , Introns , Phenotype , Retinoblastoma/diagnosis
12.
Eur J Cancer ; 41(5): 735-40, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15763650

ABSTRACT

Patients with hereditary cancer are usually diagnosed earlier than patients with non-hereditary tumours. In children with isolated unilateral retinoblastoma, some of whom have a hereditary predisposition, this rule has been subject to debate. We have analysed the clinical manifestation of disease in 188 children with completely resolved mutational status. In 24 (13%) of these patients, testing of blood DNA showed a constitutional RB1 mutation. The distribution of age at diagnosis was not different between patients with and without a constitutional mutation. However, patients with loss of the maternally inherited RB1 allele had an earlier age at diagnosis than patients with loss of the paternally inherited RB1 allele. Our data show that early age at diagnosis does not identify patients with isolated unilateral retinoblastoma that have a higher risk of being carriers of a RB1 gene mutation. Our findings suggest that, at least in some patients, age at diagnosis is modified by a parent-of-origin effect.


Subject(s)
Genes, Retinoblastoma/genetics , Mutation/genetics , Parents , Retinal Neoplasms/genetics , Retinoblastoma/genetics , Age of Onset , DNA Mutational Analysis , Genetic Predisposition to Disease , Humans , Infant , Loss of Heterozygosity , Polymerase Chain Reaction/methods
14.
J Biomed Mater Res A ; 64(2): 357-64, 2003 Feb 01.
Article in English | MEDLINE | ID: mdl-12522823

ABSTRACT

A porous polymer is required to sustain corneal epithelial tissue on the anterior surface of an implantable contact lens (corneal onlay). Porosity creates topography on the polymer surface and, if defined, this can be manipulated to elicit a particular tissue response. Previous work identified pores of 100-nm diameter to be the critical size of a discontinuity in a polymer surface to facilitate the migration, stratification, and sustained adhesion of corneal epithelial tissue. Now we address the issue of pore density. Corneal epithelial tissue was grown for 21 days on nonporous polycarbonate and polycarbonate track-etched with pores 100-nm diameter with pore densities ranging from 0.27 and 14.4% of the total polymer surface area. Histology was used to score epithelial structure, and electron microscopy was used to quantitate the formation of adhesive structures (basal lamina and hemidesmosomes) at the tissue-polymer interface. Data showed that epithelial tissue stratified and epithelial adhesive structures formed on polycarbonate surfaces with pore densities between 0.52 and 14.4% inclusive. This means that epithelial tissue can be maintained on a polymer where up to 14.4% of the surface is dedicated to small discontinuities in the form of pores 100-nm diameter. These figures can be used to specify the design of a polymer for applications requiring epithelial cover.


Subject(s)
Biocompatible Materials , Cornea/physiology , Polymers , Animals , Cattle , Cell Adhesion , Cornea/cytology , Cornea/ultrastructure , Culture Techniques , Epithelial Cells/physiology , Epithelial Cells/ultrastructure , Microscopy, Electron , Polycarboxylate Cement , Porosity , Surface Properties , Tissue Fixation
15.
Int Endod J ; 35(6): 505-13, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12190907

ABSTRACT

AIM: The purpose of this study was to compare the shaping ability of FlexMaster rotary nickel-titanium instruments with stainless steel hand K-Flexofiles. This part of the two-part report describes the efficiency of these two instruments in simulated curved root canals. METHODOLOGY: Simulated 28 degree- and 35 degree-curved canals were prepared by the FlexMaster instruments with a rotational speed of 250 rpm using a crown-down preparation technique. and by the K-Flexofiles using a reaming motion (n = 24 canals in each case). All canals were prepared up to size 35. The pre- and post-instrumentation images were recorded and assessment of the canal shape was completed with a computer image analysis program. The material removal was measured at 20 measuring points, beginning 1 mm away from the apex. Incidence of canal aberrations, preparation time,changes of working length and instrument failures were also recorded. RESULTS: In comparison with stainless steel K-Flexofiles, the rotary FlexMaster instruments achieved bet-ter canal geometry, showed less canal transportation and created fewer canal aberrations in both the canal types. Two FlexMaster instruments were separated, and 15 FlexMaster instruments and 11 K-Flexofiles were permanently deformed during preparation. However, these differences were not significant (P > 0.05). Between both the canal types, FlexMaster was significantly faster (P < 0.001) than K-Flexofiles. Both instruments maintained a good working distance. CONCLUSIONS: FlexMaster instruments prepared curved canals rapidly, and with minimal transportation towards the outer aspect of the curve.


Subject(s)
Dental Instruments , Root Canal Preparation/instrumentation , Efficiency , Equipment Design , Equipment Failure , Humans , Models, Dental , Nickel , Stainless Steel , Statistics, Nonparametric , Time Factors , Titanium
16.
Int Endod J ; 35(6): 514-21, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12190908

ABSTRACT

AIM: To determine the cleaning effectiveness and the shaping ability of FlexMaster nickel-titanium rotary instruments and stainless steel hand K-Flexofiles during the preparation of curved root canals in extracted human teeth. METHODOLOGY: A total of 48 root canals with curvatures ranging between 25 degrees and 35 degrees were divided into two groups of 24 canals. Based on radiographs taken prior to the instrumentation with the initial instrument inserted into the canal, the groups were balanced with respect to the angle and the radius of canal curvature. Canals were prepared by FlexMaster instruments using a crown-down preparation technique or by K-Flexofiles using a reaming working motion up to size 35. After each instrument, the root canals were flushed with 5 mL of a 2.5% NaOCl solution and at the end of instrumentation with 5 mL of NaCl. Using the pre- and post-instrumentation radiographs, straightening of the canal curvatures was determined with a computer image analysis program. After splitting the roots longitudinally, the amount of debris and smear layer were quantified on the basis of a numerical evaluation scale, using a scanning electron microscope. RESULTS: Completely cleaned root canals were not found with any of the two instruments. In general, K-Flexofiles resulted in significantly less debris(P < 0.001) and less smear layer (P < 0.05) than Flex-Master instruments, but these differences were not significant in the apical third of the canals (P > 0.05). FlexMaster instruments maintained the original canal curvature significantly better (P < 0.0001) than K-Flexofiles. No significant differences were detected between the instruments (P > 0.05) for the time taken to prepare the canals. CONCLUSIONS: Under the conditions of this study, K-Flexofiles allowed significantly better canal cleaning than FlexMaster instruments. FlexMaster instruments maintained the original curvature significantly better.


Subject(s)
Dental Instruments , Dental Pulp Cavity/anatomy & histology , Root Canal Preparation/instrumentation , Efficiency , Humans , Microscopy, Electron, Scanning , Nickel , Smear Layer , Stainless Steel , Titanium
17.
Eur J Hum Genet ; 9(9): 690-4, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11571558

ABSTRACT

Hereditary predisposition to lipomas is observed in familial multiple lipomatosis (OMIM 151900) and benign cervical lipomatosis (OMIM 151800) and can also be associated with mutations in the MEN1 and PTEN genes (OMIM 131100 and 153480, respectively). In addition, a recent report indicates that a few patients with hereditary retinoblastoma also have lipomas. Here we report on an extended family segregating a splice site mutation in the RB1 gene. Almost all adult carriers of this mutation had multiple lipomas while penetrance for retinoblastoma was incomplete. In an unrelated pedigree, which was reported previously, the identical mutation was only associated with low-penetrance retinoblastoma but not lipomas. Our data indicate that lipoma predisposition in hereditary retinoblastoma is not associated with specific RB1 gene mutations but is influenced by modifying factors linked to this gene.


Subject(s)
Lipomatosis, Multiple Symmetrical/genetics , Retinoblastoma Protein/genetics , Retinoblastoma/genetics , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 13/genetics , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Family Health , Female , Genetic Predisposition to Disease , Humans , Lipomatosis, Multiple Symmetrical/complications , Lod Score , Male , Mutation , Pedigree , Penetrance , Retinoblastoma/complications
18.
Hum Genet ; 108(2): 98-104, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11281459

ABSTRACT

Although it is established that the loss of function of both alleles of the RB1 gene is a prerequisite for the development of retinoblastoma, little is known about the genetic events that are required for tumor progression. We used comparative genomic hybridization (CGH) to search for DNA copy number changes in isolated unilateral retinoblastomas. From a series of 66 patients with retinoblastomas with somatic mutations in both RB1 alleles, tumor samples from 13 children with the youngest (2.0-9.8 months) and 13 with the oldest (36.2-84.1 months) age at operation were studied. Loss at 13q14, the location of RB1, was demonstrated in two tumors only. Recurring chromosome imbalances included gains at 6p (11/26), 1q (10/26), 2p (4/26), and 17q (4/26), gains of the entire chromosome 19 (3/26), and losses at 16q (9/26). A commonly gained region at 1q32 was identified. Increased dosage of GAC1, a candidate oncogene located in 1q32, was found in two of four tumors by Southern blot analysis. Comparison of the CGH findings revealed that retinoblastomas from children with an older age at operation showed significantly more frequent (13/13 cases vs 4/13 cases; P = 0.0005) and more complex genetic abnormalities (median, 5 changes/abnormal tumor vs median, 1.5 changes/abnormal tumor; P = 0.003) than retinoblastomas from children with a young age at operation. Gains at 1q, 2p, 17q, of the entire chromosome 19 and losses of 16q were restricted to the older age group. Our results suggest that the progression of retinoblastomas from older patients follows mutational pathways different from those of younger patients.


Subject(s)
Eye Neoplasms/genetics , Genes, Retinoblastoma , Nucleic Acid Hybridization , Retinoblastoma/genetics , Blotting, Southern , Child , Child, Preschool , Female , Humans , Infant , Male
19.
Cancer Res ; 61(8): 3439-42, 2001 Apr 15.
Article in English | MEDLINE | ID: mdl-11309305

ABSTRACT

Uveal melanoma is the most common form of primary eye cancer. Monosomy 3, which is an unusual finding in tumors but is present in approximately 50% of uveal melanomas, is significantly correlated with metastatic disease. To obtain positional information on putative tumor suppressor genes on this chromosome, we have investigated tumors from 333 patients by comparative genomic hybridization, microsatellite analysis, or conventional karyotype analysis. A partial deletion of the long arm was found in eight tumors, and the smallest region of deletion overlap (SRO) spans 3q24-q26. We found six tumors with a partial deletion of the short arm and were able to define a second SRO of about 2.5 Mb in 3p25. This SRO does not overlap with the VHL gene. Our finding suggests a role for two tumor suppressor genes in metastasizing uveal melanoma and may explain the loss of an entire chromosome 3 in these tumors.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 3 , Genes, Tumor Suppressor , Ligases , Melanoma/genetics , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Uveal Neoplasms/genetics , Genes, Overlapping , Humans , Karyotyping , Microsatellite Repeats , Nucleic Acid Hybridization , Polymorphism, Genetic , Proteins/genetics , Von Hippel-Lindau Tumor Suppressor Protein
20.
Cancer Genet Cytogenet ; 122(1): 13-7, 2000 Oct 01.
Article in English | MEDLINE | ID: mdl-11104026

ABSTRACT

In uveal melanoma, monosomy 3 is strongly associated with metastic disease and poor prognosis. Cytogenetic analysis and comparative genomic hybridization (CGH) have been used to identify chromosomal aberrations in uveal melanoma. As these methods are costly and time consuming in routine diagnostic settings, we evaluated whether tumors with monosomy 3 can be reliably identified by microsatellite analysis (MSA). In addition, we also tested if aberrations of chromosomes 6 and 8, which have also been associated with the course of the disease, can be detected by MSA. We established a protocol for MSA of 23 markers, 3-4 on each arm of chromosomes 3, 6, and 8. Twenty tumors were analyzed by CGH and MSA, and 10 tumors were analyzed by MSA only. For chromosome 3, the results of CGH and MSA were concordant, thus indicating that the dosage of this chromosome can reliably be determined by MSA. However, MSA failed to detect copy number gains at 6p in some tumors. Moreover, despite quantitative evaluation of allele ratios, it was not possible to discern 8p losses and gains reliably. We thus conclude that while MSA can be used to determine monosomy 3 in uveal melanoma, careful interpretation of results for chromosomes 6 and 8 is recommended.


Subject(s)
Chromosome Aberrations , Chromosomes, Human , Melanoma/genetics , Microsatellite Repeats/genetics , Uveal Neoplasms/genetics , Chromosomes, Human, Pair 3 , Chromosomes, Human, Pair 6 , Chromosomes, Human, Pair 8 , Humans , Nucleic Acid Hybridization
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