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)

Malignant brain tumors have been reported to occur in survivors of childhood acute lymphoblastic leukemia (ALL) more frequently than in the noncancer control population. The strongest risk factor seems to be cranial radiotherapy, used as central nervous system (CNS) prophylaxis. We report the case of a 9-year-old girl affected with metastatic medulloblastoma that developed 6 years after a diagnosis of acute lymphoblastic leukemia. CNS prophylaxis for ALL consisted of intrathecal methotrexate plus cytarabine (20 administrations) and 4 courses of high-dose methotrexate (5g/m2). No prophylactic cranial radiotherapy was administered. The child, in first complete remission, was well until the occurrence of a second tumor. She was treated for medulloblastoma with craniospinal radiotherapy and chemotherapy. At present, she is alive but with disease. As the unusual association of these 2 malignancies in this patient, the p53 status was investigated using FISH analysis by specific DNA probe; no p53 mutation was detected.
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PMID:Medulloblastoma as a secondary malignancy after radiotherapy-free treatment for acute lymphoblastic leukemia. 1284 25

Classical and desmoplastic medulloblastomas (MBs) have been suspected to be biologically different, though comparative studies on markers of biological aggressiveness in these two variants are sparse in the literature. 87 classical and 43 desmoplastic variants of MB were studied with respect to clinical and histological characteristics, MIB-1 labeling index (MIB-1 LI), apoptotic index (AI), ratio of AI to MIB-1 LI, expression of p53 and Bcl-2 protein and 3-year progression-free survival. The only differences documented between the variants were with regard to age distribution and location. Thus, classical histology cases occurred predominantly in children and 80% were midline in location. In contrast, lateral location was seen more frequently with tumors of desmoplastic histology, which occurred in an almost equal distribution between children (56%) and adults (44%). No difference was noted between the variants with regard to proliferation index, apoptotic index, their ratio on or their molecular controls (p53 and Bcl-2). This was reflected in the clinical outcome wherein no significant difference was observed in the 3-year progression-free survival between the variants. It is concluded that the two histological variants of medulloblastoma are not different with regard to biological parameters of aggressiveness. The growth rate and clinical outcome in medulloblastomas have no correlation with the histological variant.
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PMID:A comparative study of classical vs. desmoplastic medulloblastomas. 1286 11

Polyomaviruses are implicated in a number of cancers, and the transforming activity of their early protein, large T-antigen, has been documented in a variety of cell types and in experimental animals (1). Although the pathways by which T-antigen induces uncontrolled cell growth are not fully defined, T-antigen mediated inactivation of tumor suppressors, p53 and pRB, is well-documented in some malignancies (2). Here we postulate that functional interaction between the insulin-like growth factor (IGF-IR) and the T-antigen of human polyomavirus JC (JCV T-antigen) may contribute to the process of malignant transformation in medulloblastomas: (i) the IGF-IR signaling system is strongly activated in medulloblastoma cell lines and medulloblastoma biopsies; (ii) the cytoplasmic protein, insulin receptor substrate 1 (IRS-1), is translocated to the nucleus in the presence of JCV T-antigen; (iii) molecular characterization of the interaction between IRS-1 and JCV T-antigen indicates that the binding involves the N-terminal portion of IRS-1 (PH/PTB domain) and the C-terminal region of JCV T-antigen (aa 411-628); and finally (iv) competition for the IRS-1-JCV T-antigen binding attenuates anchorage-independent growth of T-antigen positive medulloblastoma cells in culture. Based on these findings, we propose a novel role for IRS-1 in JCV T-antigen-mediated deregulation of cellular equilibrium, which may involve uncoupling of IRS-1 from the surface receptor and translocation of its function to the nuclear compartment of the cell.
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PMID:T-antigen of human polyomavirus JC cooperates withIGF-IR signaling system in cerebellar tumors of the childhood-medulloblastomas. 1289 76

A number of recent studies have reported the detection of the ubiquitous human polyomavirus, JC virus (JCV), in samples derived from several types of neural as well as non-neural human tumors. The human neurotropic JCV was first identified as the etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually occurs in individuals with defects in cell-mediated immunity, including AIDS. However, upon mounting evidence of the oncogenic potential of the viral regulatory protein, T-antigen, and JCV's oncogenecity in a broad range of animal models, studies were initiated to determine its potential involvement in human carcinogenesis. Initially, the most frequently observed tumors in rodent models, including medulloblastoma, astrocytoma, glioblastoma, and other neural-origin tumors were analysed. These studies were followed by analysis of non-neural tumors such as colorectal carcinomas. In a subset of each tumor type examined, JC viral genomic DNA sequences could be detected by PCR and confirmed by Southern blot hybridization or direct sequencing. In a smaller subset of the tumors, the expression of T-antigen was observed by immunohistochemical analysis. Owing to the established functions of T-antigen including its ability to interact with tumor suppressor proteins such as Rb and p53, and its ability to influence chromosomal stability, potential mechanisms of JCV T-antigen-mediated cellular dysregulation are discussed. Further, as increasing evidence suggests that T-antigen is not required for maintenance of a transformed phenotype, a hit-and-run model for T-antigen-induced transformation is proposed.
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PMID:Human neurotropic polyomavirus, JCV, and its role in carcinogenesis. 1291 Feb 55

Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptc1 haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kip1, Ink4d, or Ink4c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma. To identify genes important for this tumor, we evaluated gene expression profiles in medulloblastomas from these mice. Unexpectedly, medulloblastoma expression profiles were very similar among tumors and also to those of developing cerebellum. However, 21 genes were specifically up-regulated in medulloblastoma, including sFrp1, Ptc2, and Math1, members of signaling pathways that regulate cerebellar development. Coordinated deregulation of these same genes also occurred in a large subset of human medulloblastomas. These data identify a group of genes that is central to medulloblastoma tumorigenesis.
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PMID:A molecular fingerprint for medulloblastoma. 1450 Mar 78

We analyzed the TP53 and INK4A/ARF loci in 29 pediatric medulloblastomas. Mutually exclusive mutation in TP53, methylation of P14(ARF) or deletion of INK4A/ARF were identified in 21% (6/29) of tumors. Five of these alterations were detected in large cell/anaplastic medulloblastomas or tumors with significant anaplasia. Our data provide the first evidence that alterations within the TP53-ARF tumor suppressor pathway contribute to development of aggressive forms of medulloblastoma.
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PMID:The TP53-ARF tumor suppressor pathway is frequently disrupted in large/cell anaplastic medulloblastoma. 1496 45

Cytogenetic and molecular genetic studies have shown that deletions on the short arm of chromosome 17 distal to p53 locus are the most common genetic events in medulloblastoma. We examined the occurrences and frequencies of allelic deletions on chromosome 17p13.1-13.3 by loss of heterozygosity (LOH) analysis to investigate the possible involvement of 17p13.1-13.3 in medulloblastoma development. We also performed survival analysis to determine whether LOH analysis of 17p13.1-13.3 can be used to predict prognosis in medulloblastoma. Loss of heterozygosity was analyzed by polymerase chain reaction on chromosome 17p13.1-13.3 using three microsatellite markers, TP53 on 17p13.1, D17S796 on 17p13.1-13.2, and D17S1574 on 17p13.3, in 17 medulloblastoma DNAs extracted either from archival tissue or fresh frozen tissue specimens. Allelic deletions were detected in five of 17 informative cases (29%) on TP53, eight of 17 informative cases (47%) on D17S796, and four of 17 informative cases (24%) on D17S1574. Overall, nine of 17 cases (53%) showed LOH on chromosome 17p13.1-13.3. The 5-year progression free survival (PFS) and 5-year overall survival rates were identical (59%). The 5-year PFS for nine medulloblastoma patients with LOH on 17p13.1-13.3 was 56%, and the 5-year PFS for eight medulloblastoma patients without LOH on 17p13.1-13.3 was 63%. In our survival analysis, we did not find a significant association between survival and LOH on 17p13.1-13.3. Our results support the notion that deletions of chromosome 17p13.1-13.3 may be involved in the pathogenesis of medulloblastoma. From survival analysis, we conclude that LOH on chromosome 17p13.1-13.3 may not be a significant predictor of prognosis in medulloblastoma.
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PMID:Loss of heterozygosity analysis of chromosome 17p13.1-13.3 and its correlation with clinical outcome in medulloblastomas. 1507 46

Medulloblastoma, a primitive neuroectodermal tumor of the cerebellum, is one of the most common central nervous system malignancies of childhood. Despite aggressive multimodal therapy, including surgery, irradiation, and chemotherapy, 5-year survival rates have only approached 50-60%. To identify potential candidate genes that predict for overall survival (OS), we performed a gene expression profiling analysis in 35 newly diagnosed medulloblastoma neoplasms. Subsequently, the nine most promising candidate genes were analyzed by immunohistochemistry and fluorescence in situ hybridization on tumor tissue microarrays representing a series of 180 tumors. We found 54 genes in which expression levels predicted for unfavorable survival in medulloblastoma. In line with the gene expression profiling analysis, a positive staining for STK15 (P = 0.0006), stathmin 1 (P = 0.001), and cyclin D1 (P = 0.03) was associated with an unfavorable OS, whereas cyclin B1, DAXX, Ki-67, MYC, NRAS, and p53 showed no statistical significant effect. In comparison to clinically defined parameters such as gender, age, metastatic stage, extent of tumor resection, application of chemotherapy, and tumor grade, positive staining for STK15 was identified as an independent prognostic factor for OS (P = 0.026). Moreover, additional gene copy numbers of MYC (P = 0.003) and STK15 (P = 0.05) predicted for poor survival. The combination of gene expression profiling with tissue microarray experiments allowed the identification of a series of candidate genes that predicts for survival in medulloblastoma. Of the results highlighted by the various data analysis procedures, genes associated with cell proliferation (cyclin D1), transcription (MYC), and especially mitosis (stathmin 1, STK15) appear particularly intriguing with respect to medulloblastoma pathomechanism.
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PMID:Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. 1512 47

Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of mutations that occur in cancer-related genes in pediatric neurogenic tumors.
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PMID:Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models. 1531 89

Cerebellar liponeurocytoma, a rare, newly identified CNS neoplasm of adults, is characterized by advanced neuronal/neurocytic and focal lipomatous differentiation, low proliferative potential and a favorable clinical prognosis. Despite the different age distribution and benign biological behavior, the cerebellar liponeurocytoma shares several features with the cerebellar medulloblastoma, which may include an origin from the periventricular matrix of the fourth ventricle or the external granular layer of the cerebellum. To establish the genetic profile of cerebellar liponeurocytomas, we have formed an international consortium and collected tumor samples from 20 patients. DNA sequencing revealed TP53 missense mutations in 4 (20%) of 20 cerebellar liponeurocytomas, a frequency higher than in medulloblastomas. There was no case with PTCH, APC, or beta-catenin mutations, each of which may be present in subsets of medulloblastomas. Isochromosome 17q, a genetic hallmark of classic medulloblastomas, was not observed in any of the cases investigated by FISH analysis. cDNA array analyses were carried out on 4 cerebellar liponeurocytomas, 4 central neurocytomas, and 4 classic medulloblastomas. Cluster analysis of the cDNA expression data of 1176 genes grouped cerebellar liponeurocytomas close to central neurocytomas, but distinct from medulloblastomas. These results suggest cerebellar liponeurocytoma as a distinct tumor entity that is genetically different from medulloblastoma. Furthermore, the cDNA expression array data suggest a relationship to central neurocytomas, but the presence of TP53 mutations, which are absent in central neurocytomas, suggests that their genetic pathways are different.
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PMID:Genetic and expression profiles of cerebellar liponeurocytomas. 1544 83


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