Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comparative genomic hybridization was used to analyze 41 adult fibrosarcomas from 34 patients. Thirty-one patients showed in their tumors DNA sequence copy number changes (mean 11, range 3-25). The minimal common regions for the most frequent gains were narrowed down to 12q21 (18 cases); 12q14-q15 and 14q22 (16 cases each); 4q22, 7q31, and 14q23-q24 (15 cases each); and 4q21, 4q23-q24, 8q22, and 12q22 (14 cases each). Twenty-five high-level amplifications were observed in 12 samples. 12q21 and 18p were affected three times each; and 1p21, 4q31.3, 7p21, 12q14-q15, Xp22.1-p22.2, and Xq22-q23 two times each. Losses were less frequent than gains. Early stages of adult fibrosarcomas were characterized by frequent gains of chromosomes 2, 4q, and 14q, whereas gains of chromosomes 7 and 8q were associated with progression. Gains of 12q were frequent in all of the developmental steps of this soft-tissue sarcoma. By investigation of several tumors of the same patient, a number of corresponding changes were always detected. Adult fibrosarcomas from patients who died during the observation time showed statistically significant more frequent gains of 8q, 12q, 13q, and 15q compared to the fibrosarcomas of patients who are alive. Gains and high-level amplifications of 12q14-q22, which were the most frequent genomic imbalances, partly reflected an MDM2 amplification, indicating the importance of this region in the tumorigenesis of sarcomas. In adult fibrosarcomas, a gain of 12q22 correlated significantly (P = 0.028) with a poor overall survival rate.
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PMID:Gains of 12q are the most frequent genomic imbalances in adult fibrosarcoma and are correlated with a poor outcome. 1192 Dec 84

Few studies have investigated the loss of heterozygosity and microsatellite instability in soft tissue sarcomas. Therefore, we analyzed samples of human soft tissue sarcomas to determine the status of the chromosomal region 12q14-15, which contains the MDM2 gene encoding the well-known counterpart of the tumor suppressor p53. In addition, we determined whether an amplified MDM2 gene was present in the samples. Of the 88 soft tissue sarcoma samples, 24 (27%) showed evidence of loss of heterozygosity of markers representing 12q14-15, and 12 (14%) showed evidence of microsatellite instability. Of the 72 samples analyzed by semiquantitative polymerase chain reaction, 15 (21%) possessed an amplified MDM2 gene. Loss of heterozygosity (P =.008) and microsatellite instability (P =.035) were significantly more common in Stage I tumors than in higher stage tumors. This result indicated that these alterations occur early in soft tissue sarcoma progression and possibly define a subgroup of soft tissue sarcoma. Surprisingly, MDM2 amplification in soft tissue sarcoma patients was associated with a prognosis better than that of patients without the amplification; however, this difference was not statistically significant (P =.6). Furthermore, of the tumors with an MDM2 amplification, 40% (6/15) also experienced loss of heterozygosity at 12q14-15; in contrast, only 16% of tumors without an MDM2 amplification (9/57) underwent a loss of heterozygosity. A concomitant occurrence of deletions and amplifications resulting from deficiencies in the nonhomologous end-joining pathway could in part explain this finding.
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PMID:Loss of heterozygosity at 12q14-15 often occurs in stage I soft tissue sarcomas and is associated with MDM2 amplification in tumors at various stages. 1461 50

In this study, we characterized the chromosomal composition of an intra-abdominal soft tissue sarcoma diagnosed as a malignant fibrous histiocytoma (MFH). By applying a combination of spectral karyotyping, G-banding, and comparative genomic hybridization (CGH), this case was shown to carry large chromosome markers with material mainly from chromosomes 6 and 8. Further characterization of this unique tumor revealed high-level amplifications at the 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 regions. Using array CGH, these amplified regions were found to include MASL1 in 8p, as well s MDM2 and CDK4 in 12q, which have been shown to be amplified in MFH. Similarly, gains of 6q and 8q have also been seen in MFH. In conclusion, our study demonstrates the occurrence of large chromosome markers in MFH and suggests that the regions 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 might harbor oncogenes that could play a role in MFH's tumorigenesis. In addition, gain of 12q13 approximately q21, which is typical of well-differentiated liposarcoma, may also occur in MFH, supporting the previously suggested overlap in genetic etiologies between these two tumor types.
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PMID:Characterization of large chromosome markers in a malignant fibrous histiocytoma by spectral karyotyping, comparative genomic hybridization (CGH), and array CGH. 1504 Dec 20

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.
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PMID:Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma. 1509 8

Malignant adipose tissue tumors, also called liposarcomas, are the most common sarcoma of adult life. They may be hard to distinguish from benign adipose tissue tumors as well as from other types of sarcomas. Well-differentiated liposarcomas and myxoid liposarcomas are the two histological subtypes that have been best characterized at the genetic level. The defining genetic features of well-differentiated liposarcoma cells are supernumerary circular ("ring") and giant linear rod chromosomes. These rings and giant chromosomes contain amplification of the 12q14-15 region, including the MDM2 gene, associated with coamplification of various other chromosomal regions. In addition, they most often lack alpha-satellite centromeric sequences. The detection of MDM2 amplification is a valuable tool for the differential diagnosis between well-differentiated liposarcomas and lipomas. Dedifferentiated liposarcomas usually present with patterns of MDM2 amplification similar to those observed in well-differentiated liposarcomas. In addition, recent CGH-array studies suggest that co-amplification of MDM2 with the 6q23-25 region might be a specific feature. Myxoid and round-cell liposarcomas are characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. A rare variant translocation t(12;22) that fuses DDIT3 with EWS has also been described. The genetics of pleomorphic liposarcoma is still obscure. Pleomorphic liposarcomas show complex karyotypes with many numerical and structural chromosomal aberrations. To date, no specific molecular abnormality has been identified.
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PMID:[From cytogenetics to cytogenomics of adipose tissue tumors: 2. Malignant adipose tissue tumors]. 1524 13

A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line.
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PMID:Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction. 1571 19

Soft tissue sarcomas frequently carry p53 mutations reducing chemotherapeutical response. Especially malignant fibrous histiocytoma (MFH) reveals a reduced ifosfamide (IF) chemosensitivity when compared to other sarcoma entities. This is the first study to analyze MFH cells for the effects of IF on the expression of the pathways P16-CDK4-Rb and P14ARF-MDM2-P73 regulating cell cycle. The aim was to identify candidate genes possibly involved in the anti-apoptotic response of p53-deficient MFH cells during chemotherapy. PCR, real-time RT-PCR and confocal laser scanning microscopy were applied on primary cultures of MFH cells containing defective p53 genes. The cultures were treated with different concentrations of IF. A non-treated MFH culture served as negative control. A threshold concentration of IF (100 microM) was determined sparing the majority of the cells (99%), whereas higher IF quantities caused complete apoptosis. Data collected over a period of 48 h showed that the MFH cells surviving 100 microM IF overexpressed the kinase gene CDK4 and oncogene MDM2 by a factor of 63. A similar strong increase was observed at the protein level for both proteins. In contrast, the other proteins analyzed were not detectable. Additionally, the MFH cells induced complex patterns of MDM2 mRNA splicing and an abnormal mRNA transcript carrying a novel MDM2 missense mutation. These effects were neither observed in the non-treated culture nor in cultures completely inducing spontaneous apoptosis. Therefore, we speculate that the induction of the gene CDK4, and especially of MDM2, is involved in anti-apoptotic mechanisms of p53-negative MFH cells tolerating IF in vitro. Further experiments are necessary to test whether the novel candidate genes favor development of chemoresistance and whether MDM2 mRNA splicing variants contribute to this process in vivo.
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PMID:Analysis of central regulatory pathways in p53-deficient primary cultures of malignant fibrous histiocytoma exposed to ifosfamide. 1573 17

Soft tissue sarcomas are rare and may be a source of problems for diagnosis and treatment. Four types of genetic disorders can be distinguished: translocations, gene amplifications, mutations and complex genetic imbalances. Detection of these disorders may help in diagnosis and in determining prognosis. Detection of specific translocation is recommended in synovial sarcoma, alveolar rhabdomyosarcoma or PNET diagnosis because of therapeutic consequences; in case of rarer histologic type (low grade fibromyxoid sarcoma, clear cell sarcoma, infantile fibrosarcoma...), it may confirm the diagnosis. In some cases, some translocations have a prognostic value (alveolar rhabdomyosarcoma) whereas it is discussed in others (synovial sarcoma). The techniques used to detect these translocations are very sensitive so it may be used to detect microscopical metastasis (bone marrow metastasis of alveolar rhabdomyosarcoma for example). Detection of MDM2 and CDK4 genes amplifications (FISH or quantitative PCR) may be sometimes useful in well differentiated and dedifferentiated liposarcomas diagnosis. Mutation detection of KIT or PDGFRA may help in GIST diagnosis and type of mutation is predictive of response to treatment. Study of complex genomic imbalances in sarcomas is not used in routine practice but remains useful in research.
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PMID:[Soft tissue sarcomas: update on molecular data]. 1644 27

A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T-->G change), was recently implicated in the early onset of cancer in individuals with Li-Fraumeni syndrome and of sporadic soft-tissue sarcoma. SNP309 induces an increase in the level of Mdm2 protein, which causes attenuation of the p53 pathway. To investigate the effect of this polymorphism in colorectal cancer pathogenesis, we genotyped 153 colorectal cancer patients who were randomly selected from among 330 consecutive patients stratified according to p53 mutation status and age at diagnosis, for alleles of MDM2-SNP309. Among the 77 patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype and 61.0 years for patients with SNP309 (T/G or G/G genotype) (estimated difference between medians [Hodges-Lehmann method] = 8.0 years, 95% confidence interval = 1.0 to 16.0 years; P = .03 [two-sided Wilcoxon rank sum test]). Our data indicate that MDM2-SNP309 is a modifier of the age at colorectal cancer onset for patients whose tumors have a wild-type p53 gene.
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PMID:Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. 1647 47

From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 microM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC(50) = 5.3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.
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PMID:Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. 1703 27


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