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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inactivation of antioncogenes has been postulated to be important in the development of human malignancies. In 1986, a cDNA clone of the putative retinoblastoma antioncogene (Rb gene) has been isolated by molecular genetic approach. Recent work has shown that the neoplastic phenotype of retinoblastoma and osteosarcoma cells can be suppressed by the introduction of a cloned Rb gene. Interestingly, the product of the Rb gene has recently been shown to associate with the transforming proteins of DNA tumor viruses.
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PMID:[Antioncogene]. 265 35

The determination and comparison of genotypic combinations at genomic loci in constitutional and tumor tissues from patients with various types of cancer have defined the chromosomal locations of loci in which recessive mutations play a role in disease development. The predisposing nature of some of these mutant alleles is exemplified by studies of retinoblastoma and osteogenic sarcoma, two clinically associated diseases that share a pathogenetically causal predisposition mapping to 13q14. Genomic alteration of chromosome 10 is apparent in glioblastomas and mixed tumors of glioblastoma/astrocytoma grade III but not in homogeneous astrocytoma grades II or III; this suggests the definition of a locus involved in tumor progression and, perhaps, an approach to molecular genetic staging of tumors.
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PMID:Loss of heterozygosity in stages of malignancy. 266 35

Introduction of an exogenous retinoblastoma (RB) gene in RB-deficient retinoblastoma or osteosarcoma cells has been shown to suppress their neoplastic phenotype. In experiments designed to explore the potential mechanism of RB tumor suppression, we report here that the phosphorylation state of RB protein is modulated during normal cellular events. In resting cells, RB protein is present in its least phosphorylated form; in rapidly proliferating cells, RB protein is highly phosphorylated. Maximal phosphorylation is associated with S phase of the cell cycle. Induction of differentiation in several human leukemia cell lines by treatment with phorbol ester or retinoic acid leads to dephosphorylation of RB. Time course studies indicate that RB dephosphorylation precedes the total arrest of cell growth during differentiation. These observations strongly suggest that the function of RB protein is modulated by a phosphorylation/dephosphorylation mechanism during cell proliferation and differentiation.
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PMID:Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. 267 46

Based on the two mutation hypothesis in the development of retinoblastoma, loss of heterozygosity (LOH) of specific chromosome has been implicated in the presence of tumor suppressor gene. Studies on the LOH in different types of tumors revealed that LOH of each chromosome might play a different role in the multistep process of carcinogenesis: LOH of some chromosomes may play an etiological role in the development of some tumors, while that of other chromosomes or the same chromosome in other tumors, may play a role in the progression of tumors. LOH of chromosome 13 is an example for the former cases, and the latter cases involve LOH of chromosome 17 in colorectal carcinoma and osteosarcoma, chromosome 10 in glioblastoma, chromosome 1 in neuroblastoma and malignant melanoma, and chromosome 11 in breast carcinoma. These studies indicates that the progressive or concerted LOH could be a measure of the highly malignant or metastatic potentiality. However, it should be borne in mind that, especially in polyploid tumors, LOH also occurs as a random event following the polyploidization-segregation process.
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PMID:[Loss of heterozygosity in the progression of tumors]. 267 92

Cytogenetic analysis was performed on eight osteosarcomas, including six primary untreated biopsies, one second primary in a patient with a history of undifferentiated sarcoma, and one recurrent lung metastasis. Two primary tumors and the peripheral blood lymphocytes from all eight patients had normal karyotypes. Six of the tumors demonstrated extremely complex karyotypes, with modal numbers in the hypodiploid, triploid, and hypertetraploid ranges. The predominant types of structural abnormalities observed were nonreciprocal translocations and deletions, which differed between cases. A consistent loss of normal chromosome 13 homologs was evident in the six cases with abnormal tumor karyotypes; however, chromosomal loss was not restricted to #13. Molecular studies of osteosarcoma, especially with regard to the retinoblastoma locus on chromosome 13, should take into consideration the complex cytogenetic changes seen in this tumor.
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PMID:Complex karyotypes in a series of pediatric osteosarcomas. 271 18

Retinoblastoma and osteosarcoma arise from cells that have lost both functional copies of the retinoblastoma gene. Using the cloned retinoblastoma gene and other linked polymorphic loci, it is possible to reconstruct the sequential loss of the two homologous gene copies that precedes the development of these tumours. In non-hereditary tumours, the loss of each of the two homologues occurs somatically; in hereditary cases, the initial mutation is in the germline. Recently, Toguchida et al. reported that the paternally derived copy is preferentially the first one to become mutant during the genesis of non-hereditary osteosarcomas. We report here a similar analysis of patients with retinoblastoma in which we find no such predilection for initial somatic mutations. In contrast, when an initial mutation was a new germline mutation, it was derived from the father, a result which is consistent with new germline mutations arising primarily during spermatogenesis.
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PMID:Parental origin of mutations of the retinoblastoma gene. 273 86

The retinoblastoma (RB) susceptibility gene is one member of a putative "cancer suppressor gene" family in which loss of gene function is associated with tumor formation. Using antibodies generated against a trypE-RB fusion protein, we previously identified a nuclear phosphoprotein, pp110RB, as the RB gene product. Here we describe three additional polyclonal antibodies that were generated to separate epitopes of pp110RB with three synthetic peptides deduced from the RB cDNA sequence. All four antibodies could specifically recognize the same phosphoprotein in human cells. This protein was phosphorylated on serine and threonine, but not tyrosine, residues. RB homologous proteins with molecular masses of 105-128 kD were detected in other vertebrates, such as monkey, rodent, and chicken, by at least two antibodies, indicating evolutionary conservation of the RB gene. These antibodies were specific and sensitive for monitoring RB gene inactivation as demonstrated by screening several osteosarcoma and synovial sarcoma cell lines. Of nine cell lines examined, three expressed no immunoprecipitable normal RB protein. DNA rearrangement and abnormal RB mRNA were detected in two of these three cell lines, whereas RB protein was absent from one synovial sarcoma cell line in which normal-sized RB mRNA was clearly present. Therefore, direct immunoprecipitation of RB protein can reveal RB gene mutations that are undetectable by DNA and mRNA analysis. These results further support a crucial role for the RB gene in the oncogenesis of some mesenchymal tumors.
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PMID:Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas. 274 Jan 44

We found deletions involving the retinoblastoma gene in 12 of 49 tumors from patients with retinoblastoma or osteosarcoma. After mapping the deletion breakpoints, we found that no two breakpoints coincided. Thus, our data do not support the conclusions of others regarding the existence of a "hotspot" for deletion breakpoints in this gene. In 4 of the tumors, we sequenced 200 base pairs surrounding each deletion breakpoint. Three deletions had termini within pairs of short, direct repeats ranging in size from 4 to 7 base pairs. These results indicate that the "slipped mispairing" mechanism may predominate in the generation of deletions at this locus. Our review of deletion breakpoints at other genetic loci reveals that the nature of the sequences present at deletion breakpoints (short, direct repeats versus middle repetitive elements) varies according to the genetic locus under study.
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PMID:Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene. 274 Mar 42

The determination and comparison of genotypic combinations at genomic loci in normal and tumour tissues from patients with various types of cancer have defined the chromosomal locations of loci at which recessive mutations play a role in disease. The predisposing nature of some of these mutant alleles is exemplified in studies of retinoblastoma and osteogenic sarcoma. These two clinically associated diseases share a pathogenetically causal predisposition that maps to chromosome position 13q14. A similar mechanism at 11p15.5 is involved in the development of the embryonal variant of rhabdomyo-sarcoma, Wilms' tumour and hepatoblastoma. Finally, genomic alteration of chromosome 10 is apparent in glioblastomas and mixed tumours of glioblastoma/astrocytoma grade III but not in homogenous astrocytoma grades II or III, suggesting the definition of a locus involved in tumour progression and, perhaps, an approach to molecular genetic staging of tumours.
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PMID:Loss of genetic information in cancer. 274 36

Complete inactivation of the human retinoblastoma gene (RB) is believed to be an essential step in tumorigenesis of several different cancers. To provide a framework for understanding inactivation mechanisms, the structure of RB was delineated. The RB transcript is encoded in 27 exons dispersed over about 200 kilobases (kb) of genomic DNA. The length of individual exons ranges from 31 to 1889 base pairs (bp). The largest intron spans greater than 60 kb and the smallest one has only 80 bp. Deletion of exons 13-17 is frequently observed in various types of tumors, including retinoblastoma, breast cancer, and osteosarcoma, and the presence of a potential "hot spot" for recombination in the region is predicted. A putative "leucine-zipper" motif is exclusively encoded by exon 20. The detailed RB structure presented here should prove useful in defining potential functional domains of its encoded protein. Transcription of RB is initiated at multiple positions and the sequences surrounding the initiation sites have a high G + C content. A typical upstream TATA box is not present. Localization of the RB promoter region was accomplished by utilizing a heterologous expression system containing a bacterial chloramphenicol acetyltransferase gene. Deletion analysis revealed that a region as small as 70 bp is sufficient for RB promoter activity, similar to other previously characterized G + C-rich gene promoters. Several direct repeats and possible stem-and-loop structures are found in the promoter region. No enhancer element was detected within the 7.3 kb of upstream sequence studied. Several features of the RB promoter are reminiscent of the characteristics associated with many "housekeeping" genes, consistent with its ubiquitous expression pattern.
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PMID:Structure of the human retinoblastoma gene. 274


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