Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoblastoma (RB) tumors develop when both alleles of a gene (RB1) are mutated and unable to function normally. Recently, Friend et al. [S. H. Friend, R. Bernards, S. Rogelj, R. A. Weinberg, J. M. Rapaport, D. M. Albert, and T. P. Dryja, Nature (London) 32:643-646, 1986] reported the cloning of a gene, 4.7R, with some properties expected for the RB1 gene, namely, a high frequency (30%) of genomic rearrangements in tumors and absence of message in all RB tumors examined. To extend the characterization of this gene, we used 4.7R probes to search for genomic rearrangements of DNA and to study the expression of the 4.7R gene in RB tumors, osteosarcoma (OS) tumors arising in RB patients, and other normal and malignant tissues. In 34 previously unreported RB and OS tumors arising in RB patients, we observed only four (12%) with genomic abnormalities. Transcripts of 4.7R were present in 12 of 17 RB tumors, 2 of 2 OS tumors, and all non-RB tumors and normal tissues tested. We were unable to confirm the high frequency of truncated messages of 4.7R in RB tumors reported by Lee et al. (W. H. Lee, R. Bookstein, F. Hong, L. J. Young, J. Y. Shaw, and E. Y. Lee, Science 235:1394-1399, 1987) and Fung et al. (Y. K. Fung, A. L. Murphree, A. Tang, J. Qian, S. H. Hinrichs, and W. F. Benedict, Science 236:1657-1661, 1987) but did confirm the presence of a truncated transcript in the RB cell line Y79. Of the RB and RB-related OS tumors which appeared normal on Southern blots, 2 of 26 or 12% had abnormal transcripts, giving a combined frequency of 22% abnormalities in the 4.7R gene detectable by Southern and Northern (RNA) blot analyses.
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PMID:Infrequent genomic rearrangement and normal expression of the putative RB1 gene in retinoblastoma tumors. 289 30

Survivors of the heritable form of retinoblastoma subsequently develop second primary osteosarcomas at substantially greater frequency than either the general population or survivors of nonheritable retinoblastoma. Here we present molecular genetic evidence that the development of these two disparate tumor types involves specific somatic loss of constitutional heterozygosity for the region of human chromosome 13 that includes the RB1 locus. Similar events occur during the genesis of nonheritable osteosarcoma but not in several other embryonal tumors or sarcomas. These findings suggest that a conceptual approach toward defining the number of genes whose recessive mutant forms predispose to cancer is the molecular genetic analysis of clinically associated tumor types. They also suggest that the molecular basis of mixed cancer families may be the differential expression of a single pleiotropic recessive mutation by tissue specific mitotic segregation abnormalities.
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PMID:Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. 299 66

A strong case for a genetic diathesis in human cancer can be made through the analysis of familial aggregations of mixed tumor types. This is particularly true for childhood cancers which have a very low incidence when compared to that of adult cancer and for which common environmental factors appear to play little etiological role. Here are described studies designed to apply molecular genetic analysis toward defining the lesions which predispose to human cancer. We found that the clinically associated tumors retinoblastoma and osteosarcoma share a pathogenetic mechanism entailing aberrant chromosomal segregation events during mitosis which lead to tumor cells homozygous for recessive mutant alleles at the RB1 locus on human chromosome 13 band q14. These results suggest that a rational explanation for the sequential occurrence in these children of two different tumor types is the initial inheritance of a predisposing recessive mutation with broad but specific tissue activity.
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PMID:Chromosomal mechanisms in the initiation of human familial mixed cancers. 333 9

Among the solid tumors of childhood and adolescence, osteosarcoma (OS) represents the most prominent example of efficient aggressive chemotherapy with secondary surgical therapy. A specific subclassification of the tumor is indispensable and must include recent results of cell biology. The co-distribution of different collagen types I-VI reflects the diverse differentiation of osteosarcoma cells, supporting the concept of a pluripotent mesenchymal cell to be the stem cell of the tumor. In contrast, osteonectin (SPARC) may not be considered as a reliable marker for osteosarcoma. The experience of special proteins being secreted by osteosarcoma cells is rather limited. Detailed molecular biological studies are still lacking. A loss of alleles on chromosome 17, particularly in the defined region 17p 13, can be observed in more than 75% of all OS, suggesting the contribution of a tumor suppressor gene, p53, located in that region. It is a 53 kd nucleophosphoprotein binding the major transforming protein, the large T antigen of Simian Virus 40. Immunohistological results showed positive staining with the antibody Pab 240 in 13 of 18 cases. In one osteoblastic OS, a novel splice mutation resulting in a fusing of exon 5 directly to exon 7 was detected. RB1 gene is also of major importance for the tumorigenesis of OS. The multidrug resistance (mdr) is associated with a membrane-bound channel-forming transport protein, the P-glycoprotein. It is a conserved plasma membrane component of about 170 kd. Both the human isoforms mdr 1 and mdr 3 are localised in the long arm of chromosome 7.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New aspects of cell biology in osteosarcoma. 747 79

Human osteosarcoma and fibrosarcoma cell lines were investigated for alterations in oncogenes, tumor suppressor genes, and growth factors, all of which have been implicated in tumor formation. Characterization of oncogenes that are involved in osteosarcoma formation, including the c-fos and c-myc oncogenes, indicated that all six osteosarcoma cell lines examined had 5- to 20-fold amplification of the c-myc oncogene, whereas neither of two fibrosarcoma cell lines c-myc amplification. Interestingly, only three of six osteosarcoma cell lines displayed altered c-myc immediate-early gene function. c-fos was found to be normal, both at the gene and functional levels, in all six osteosarcoma and both fibrosarcoma cell lines tested. Characterization of two tumor suppressor genes, p53 and RB1, that have been implicated in osteosarcoma formation indicated that p53 was altered in five of six osteosarcoma cell lines, whereas RB1 was altered in only two or six of these cell lines. Neither RB1 nor p53 was found to be altered in the fibrosarcoma cell lines tested. An additional transformation marker, autocrine growth-factor production, was observed in all six osteosarcoma cell lines and both fibrosarcoma cell lines examined. Finally, the differentiation state of the osteosarcoma cell lines was investigated via the bone differentiation markers alkaline phosphates and osteocalcin. Alkaline phosphatase activity was observed in four of six osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined. The alkaline phosphatase activity was a result of the expression of the bone/liver/kidney alkaline phosphatase isoform. High-level osteocalcin expression was observed in one of the osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined, although all cell lines demonstrated low-level osteocalcin expression. Together, these data demonstrate that relatively undifferentiated osteosarcomas commonly display c-myc amplification, p53 and RB1 mutation, and autocrine growth-factor production, all of which may play a role in osteosarcomagenesis.
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PMID:Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines. 757 9

We have established a stable PCR system and studied the structural anomalies of RB gene by it in osteosarcoma, previous studies have proved that 13-17 exons of RB gene are the deletion hotpoints. We designed a pair of perimers, RB1, RB2 stretching across 14-16 exons and studied 10 cases of osteosarcoma. No structural anomaly was found in the leucocyte. Two cases (20%) showed no PCR product. This result demonstrates for the first time the deletion of RB gene is present in Chinese osteosarcoma patients.
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PMID:[Detection of RB gene in osteosarcoma by PCR]. 803 99

A 24-year-old male patient with hereditary retinoblastoma and a poorly differentiated osteoblastic osteogenic sarcoma was found to carry a mutant RB1 allele in all cells. This findings was most likely a point mutation or microdeletion because Southern blot analysis of peripheral blood DNA failed to disclose any structural aberration of the RB1 gene. A somatic mutation (deletion) affecting the other allele was found in the osteosarcoma cells. Management of tumor by external radiotherapy in early age is questioned because the effect of irradiation is to significantly increase the total incidence of second tumors above the already high incidence in non-irradiated patients.
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PMID:An association of the RB gene with osteosarcoma: molecular genetic evaluation of a case of hereditary retinoblastoma. 821 29

The retinoblastoma gene product, p110RB1, appears to regulate cell growth by modulating the activities of nuclear transcription factors. The elements that specify the transport of p110RB1 into the nucleus have not yet been explored. We now report the identification of a basic region, KRSAEGGNPPKPLKKLR, in the C terminus of p110RB1, which has sequence similarity to known bipartite nuclear localization signals (NLSs). A two-amino-acid mutation introduced into this putative NLS [to give mutant NLS(NQ)] or deletion of the entire NLS (delta NLS) abrogated exclusive nuclear localization, yielding proteins which were distributed either equally throughout the cell or predominantly in the cytoplasm. A mutant protein [NLS(NQ)/delta 22] containing both the mutated NLS and a deletion of exon 22, previously shown to disrupt the interaction of p110RB1 with several cellular transcription factors and oncoproteins, accumulated only in the cytoplasm. When fused to the C terminus of Escherichia coli beta-galactosidase, the RB1 NLS directed this protein to the nucleus, indicating that the motif is not only necessary but also sufficient for nuclear transport. Neither NLS(NQ) nor delta NLS was hyperphosphorylated in vivo, but both retained their abilities to interact, in vitro, with simian virus 40 large T antigen, adenovirus E1a, and the cellular transcription factor E2F. When transfected at multiple copy number, the NLS mutant alleles displayed reduced biological activity, measured by inhibition of growth of the osteogenic sarcoma cell line Saos-2, which has no wild-type RB1. Naturally occurring mutations and deletions in exon 25 of RB1 which disrupt the NLS may lead to partial or complete inactivation of p110RB1 and may be responsible for some retinoblastoma and other tumors.
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PMID:A bipartite nuclear localization signal in the retinoblastoma gene product and its importance for biological activity. 833 4

Studies of retinoblastoma clearly identify mutation of the RB1 gene on chromosome 13 as the primary cause of this cancer. However, all retinoblastoma tumors have an abnormal karyotype (1, 2) indicating the presence of additional mutations and suggesting that mutation of both RB1 alleles is insufficient for development of retinoblastoma. In addition, analysis of RB1 expression and of RB1 mutations in different tumors leads to the following dilemma: while the RB1 gene product, p110RB1, is expressed in most dividing cells, germline mutations inactivating the function of p110RB1 predispose primarily to retinoblastoma and to a lesser extent to osteosarcoma, but do not predispose to cancer in general. However, many tumors contain somatic mutations that disrupt RB1 function. Thus, we are faced with the unusual situation in which germline mutations in the RB1 gene predispose to a very limited set of cancers, but somatic mutations in RB1 appear to contribute to malignancy in many tissues. We propose that the role of the RB1 gene is to maintain the cells in a stable, quiescent state required for terminal differentiation and that the effect of RB1 mutations in different tissues depends on the pattern of differentiation in that tissue. In tissues where differentiation follows a linear process from undifferentiated precursors to fully differentiated cells, loss of RB1 function during early stages of differentiation may lead to uncontrolled growth and the development of cancer. On the other hand, in cell renewal systems where cell number is usually maintained by a process of programmed cell death (PCD) or apoptosis, loss of RB1 function may lead to cell death.
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PMID:Speculations on the roles of RB1 in tissue-specific differentiation, tumor initiation, and tumor progression. 834 84

The cytogenetic analysis of a radiation-induced osteosarcoma in a 31-year-old male is presented. Complex karyotypic changes with numerical and structural abnormalities, including a del(13)(q12.3q21.1), were observed. This deletion may indicate that loss of RB1 gene (locus in 13q14) may be involved in the development of radiation-induced osteosarcoma.
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PMID:Deletion of chromosome 13 in osteosarcoma secondary to irradiation. 837 97


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