Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three rare cases of familial aggregation of soft tissue sarcomas (malignant fibrous histiocytoma in a mother and liposarcomas in her two children) are described. The mother developed a late onset of malignant fibrous histiocytoma in her right thigh. Her son and daughter both developed retroperitoneal liposarcomas at the ages of 38 and 33 years, respectively. The mother also developed gastric carcinoma as a second malignancy after a 2-year interval. These clinical features closely resemble those of Li-Fraumeni syndrome, but do not fulfill the exact diagnostic criteria. Genetically, the germline mutation of the p53 gene between exons 4 and 9 was not detected by sequencing DNA obtained from the peripheral blood of the mother. Immunohistochemically, p53 protein was found only in the liposarcoma of the daughter. These results strongly suggest that this familial aggregation of soft tissue sarcomas is very rare, and that it is a unique feature of a familial cancer syndrome that to our knowledge has not been defined or described previously.
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PMID:Familial aggregation of soft tissue sarcomas: a report of three cases from a Li-Fraumeni-like family. 916 3

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.
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PMID:Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma. 940 3

Cytogenetic and molecular analysis of soft tissue tumours has yielded a wealth of new information over the past 10-15 years. Many soft tissue neoplasms show specific karyotypic aberrations which have proved to be diagnostically valuable, and have also assisted in the understanding of pathogenetic mechanisms and rationalisation of classification systems (e.g. lipomatous tumours and Ewing's sarcoma/PNET). In certain clinical subsets, especially round cell sarcomas and fatty neoplasms, determination of karyotype (whether by conventional analysis, FISH or RT-PCR) has proved often to be useful in the diagnostic setting. Additionally the recognition of clonal abnormalities in both benign neoplasms as well as lesions formerly thought to be non-neoplastic (e.g. inflammatory "pseudotumour") has prompted reassessment of biologic concepts with regard to growth control. Inherited molecular genetic defects which predispose to soft tissue neoplasia (e.g. NF-1, Li-Fraumeni syndrome) have been characterised, leading to a greater understanding of tumour suppressor genes. Mesenchymal differentiation genes, the modes of action of which may help to expunge concepts of histogenesis, are being characterised. It is becoming clear that there exist growth control genes (such as the HMGI family) which, irrespective of differentiation, play an important role in a wide range of different mesenchymal tumours. Additionally it is evident that different histologic types of sarcoma (e.g. variants of liposarcoma) show quite different abnormalities of cell cycle control (notably at the G1-S checkpoint) and it seems increasingly likely that certain genetic aberrations, identifiable either at the chromosomal or individual gene level, may prove to be of prognostic relevance in sarcomas and may also open novel therapeutic avenues. While the validity of all molecular genetic data depends totally on skilled histological diagnosis and grading, there has never been a better time for close collaboration between pathologists and basic scientists in the study of soft tissue neoplasia.
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PMID:Soft tissue tumours: the impact of cytogenetics and molecular genetics. 947 86

Acral myxoinflammatory fibroblastic sarcoma is a unique low-grade tumor of modified fibroblasts. It characteristically occurs in the distal extremities and has a propensity to recur locally. Forty-four cases that occurred in 22 males and 22 females from 20 to 91 years of age (median, 53 years) were studied. The lesions, which were 1-6 cm (median, 3 cm), occurred in the hands (64%), the feet (20%), the ankles (11%), and the wrists (5%). The patients usually had a long history of a painless mass (median duration, 1 year). Clinically they were suspected to be ganglion cysts, tenosyonovitis, or giant cell tumors of tendon sheath. Initial histologic diagnoses, in most cases, included pigmented villonodular tenosynovitis or various reactive fibroinflammatory processes. Histologically, the lesions were multinodular, poorly delineated, and characterized by a prominent myxoid matrix containing numerous inflammatory cells, including polymorphonuclear leukocytes, eosinophils, lymphocytes, and plasma cells, as well as fibrosis. Amidst the prominent inflammation, and sometimes obscured by it, were scattered, large, bizarre tumor cells with vesicular nuclei, prominent inclusion-like nucleoli, and abundant eosinophilic cytoplasm, which was homogeneous to vacuolated and often contained intracytoplasmic inflammatory cells. Ultrastructurally, the bizarre tumor cells had features of modified fibroblasts, including an abundance of intermediate filaments and dilated rough endoplasmic reticulum. Immunohistochemically, the neoplastic cells revealed strong positivity for vimentin (25 of 25), focal positivity for CD68 antigen (17 of 25) and CD34 (7 of 25); the tumor cells did not express neuroectodermal, epithelial, or lymphoid markers. The Ki67 labeling index with MIB1 was less than 1% in 20 of 25 cases; p53 immunoreactivity (20-90%) was observed in 7 of 25 primary tumors and in 2 of 3 local recurrences. Follow-up information was available in 36 of 44 cases (median, 5 years). Most excisions were either intralesional or marginal. Ten patients underwent amputation, usually after repeated local recurrences. Radiation therapy and chemotherapy were administered in five and two cases, respectively. Twenty-four cases (67%) had at least one local recurrence. A histologically proven lymph node metastasis developed in one patient, whereas another was stated to have lung metastases, although these were not documented histologically. At last follow-up, 23 patients were alive and well, 11 were alive with disease, and 2 were dead of other causes without evidence of tumor. The prominent inflammation and fibrosis seen histologically in acral myxoinflammatory fibroblastic sarcoma simulate a reactive process. The presence of myxoid foci and scattered bizarre cells, which are occasionally multivacuolated, may cause confusion with malignant fibrous histiocytoma and liposarcoma. Based on the protracted clinical course, a high rate of local recurrence (sometimes necessitating amputation), and a low rate of metastasis, we believe these tumors are low-grade sarcomas. The intimate relationship with the synovium, the frequent association with tenosynovitis, and the prominent inflammatory infiltrate suggest that inflammation may play a role in the pathogenesis of acral myxoinflammatory fibroblastic sarcoma.
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PMID:Acral myxoinflammatory fibroblastic sarcoma: a low-grade tumor of the hands and feet. 970 71

It has recently been shown that mdm2 overexpression with stabilization of p53 represents a characteristic of retroperitoneal well-differentiated-dedifferentiated, here renamed evolved (WD-E), liposarcomas at the immunocytochemical, molecular, and cytogenetic level. This make-up appears to be confined to half the cases in non-retroperitoneal well-differentiated liposarcomas. Since in different tumours MDM2 amplification involves amplicons encompassing flanking genes, such as CDK4, the possibility was investigated that in these tumours, CDK4 could act as an alternative or additional gene involved in the transformation mechanism. Forty-one retroperitoneal (R)/non-retroperitoneal (NR) well-differentiated-dedifferentiated (WD-DD) and 33 myxoid/round cell liposarcomas were reanalysed by immunocytochemical, molecular (nine cases) and fluorescence in situ hybridization (FISH) (one case) techniques. The results showed that all but one R WD-E cases carried the mdm2+, p53+, cdk4+ immunophenotype. In NR-WD liposarcomas, this immunophenotype was shared in five cases and the remainder showed mdm2+, p53-, cdk4+ in four and mdm2-, p53-, cdk4+ in one case, showing ring chromosomes by FISH analysis. TP53 mutations are confirmed to be closely correlated with NR-DD liposarcomas and no CDK4 involvement was found in the myxoid/round cell liposarcoma group. As well as confirming the synergistic effect of MDM2 and CDK4, these results are consistent with the concept that amplicon(s) excluding MDM2 may contribute to transformation and support a role of CDK4 in opposing p53 function, particularly in NR WD liposarcoma.
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PMID:Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22. 971 46

Although it is well known that oncogenesis is a multistep process involving the activation of normal cellular genes to become oncogenes and/or the inactivation of tumor suppressor genes, this process has seldom been investigated in soft tissue tumours. We screened a group of 36 liposarcomas for genetic abnormalities in the p53 tumour suppressor gene and c-myc oncogene. Altered c-myc gene expression was examined by differential RT-PCR assay. p53 Gene mutations in exons 4-8 were analysed by using PCR-SSCP analysis and direct sequencing. Elevated c-myc expression was found in 6 of 31 liposarcomas (19.4%). p53 Gene mutations were observed in 5 of 36 liposarcomas (13.9%). Both genetic alterations were associated with the histological subtype of liposarcomas. Whereas c-myc gene expression was a characteristic of myxoid/round cell liposarcomas, p53 gene mutations were found more frequently in pleomorphic variants. Liposarcomas of the well-differentiated subtype showed neither p53 gene mutations nor altered c-myc gene expression. Our results indicate that the c-myc oncogene and the p53 tumor suppressor gene do not seem to cooperate in the oncogenesis of liposarcomas.
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PMID:No correlation of c-myc overexpression and p53 mutations in liposarcomas. 980 33

A continuously growing cultured cell line has been obtained in vitro, starting from a specimen of ascites fluid obtained from a patient with ovarian cancer, in whom a poorly-differentiated adenocarcinoma was diagnosed. This cell line, named OC-A1, is routinely grown in standard, serum-supplemented culture medium and has been fully stabilized to long-term growth and characterized for both cultural and genetic parameters. OC-A1 cells express a set of characteristics, as determined in vitro which, when compared with the in vivo primary tumor, confirm the high malignity of this cancer. In addition, karyotype analysis showed a translocation of chromosome 8 which is correlated with the amplification of c-myc oncogene. However, the expression of this oncogene was found to be significantly inhibited by a new regulatory activity, recently found to be present in a liposarcoma cell line. Conditioned medium from these cells was indeed able to inhibit the growth of OC-A1 cells, arresting their cell cycle in the G1 phase and inducing them to apoptosis. Finally, the cell programmed death appeared to be related to the expression of antioncogene p53.
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PMID:Establishment and growth regulation of a novel ovarian cancer cell line from a poorly-differentiated adenocarcinoma: proposal for a new treatment. 1042 82

Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-alpha on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-alpha, irrespective of p53 status, inhibited the proliferation of all five cell lines dose- and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-alpha and RAR-beta mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-gamma, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-alpha or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result from different mechanisms which differ in their dependence upon the presence of intact p53.
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PMID:Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-alpha and retinoids. 1042 35

We describe 12 patients with a distinctive variant of pleomorphic liposarcoma that histologically shows epithelioid features and focally resembles a solid carcinoma. The tumors occurred in nine men and three women (median age, 63 yr; range, 40-78 yr). Five tumors were in the thigh, two in the chest wall, two in the axilla, and one each in the retroperitoneum, groin, and calf. Most were 15 to 20 cm in maximal diameter. They consisted of sheets of epithelioid-appearing cells with ample, variably eosinophilic cytoplasm, often showing a honeycomb-like pattern of cell borders and little if any collagenous extracellular matrix. Their histologic features often resembled those of renal clear cell carcinoma or adrenal cortical carcinoma, but all showed evidence of adipocytic differentiation, and five also showed focal spindle cell components. One patient whose tumor in the thigh had been originally diagnosed as metastatic renal carcinoma had undergone nephrectomy without a finding of a kidney tumor. All of the cases were positive for vimentin; 6 of 11 cases were positive for S-100 protein, usually focally; 5 of 11 were focally positive for keratins; and all were negative for epithelial membrane antigen, muscle actins, desmin, and CD34. High mitotic activity (mean, 42 mitotic figures per 10 high power fields) and high MIB-1-positive proliferative fraction (>30%) were seen in all of the cases, and nuclear p53 immunoreactivity was detected in five of seven cases. Of the eight patients with complete follow-up, five died of disease (median survival, 6 mo), two died of unrelated causes 10 and 18 years later, and 1 was alive and well 24 years later. The epithelioid variant of pleomorphic liposarcoma is a high-grade tumor that must be distinguished from malignant epithelial tumors, especially in view of the keratin immunoreactivity of some of these neoplasms.
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PMID:Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma. 1043 Feb 77

Recent observations indicate the existence of pathogenetically distinct groups of well-differentiated (WD) dedifferentiated (DD) liposarcomas. In the retroperitoneal WD-DD liposarcomas, the predominant phenotype is represented by the aberrant (overexpressed) mdm2+/p53+ wild-type profile. At the nonretroperitoneal site, the WD liposarcomas present a wider association of MDM2/P53 gene expression; i.e., mdm2+/p53+, mdm2+/p53-, mdm2-/p53+ and mdm2-/p53-, and TP53 mutations seem to correlate with the dedifferentiation process. A biochemical study of mdm2-p53 association in 11 tumor samples characterized by the presence of different mdm2 and p53 immunophenotypes was performed. Immunoprecipitation assays using a p53-specific antibody were performed on tumor tissue and surrounding normal tissue; the immunoprecipitated material was then investigated for the presence of p53 (control) and of coimmunoprecipitated mdm2. This biochemical analysis showed that, in mdm2+/p53+/wild-type retroperitoneal liposarcomas, a band corresponded to mdm2 protein in the cellular lysates immunoprecipitated with a p53-directed antibody. In contrast, the mdm2+/p53- liposarcoma did not evidence the presence of mdm2 protein nor was p53 protein available to direct immunoprecipitation, as in the p53 mutant tumor samples with mdm2-/p53+ and mdm2-/p53- phenotypes. From the normal counterpart of retroperitoneal liposarcoma lysates, no p53 protein was immunoprecipitated. The findings in this study agree with the molecular data and they show the physical association of mdm2 and p53 in fresh liposarcoma surgical specimens.
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PMID:Biochemical uncovering of mdm2/p53 complexes in liposarcomas parallels their immunohistochemical detection. 1056 83


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