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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytogenic and molecular genetic analyses of the major histological subtypes of nervous system tumors, gliomas, meningiomas, and neurinomas, have provided interesting information on the mechanisms responsible for or contributing to their origin and development. Regarding malignant gliomas, a complex pattern of chromosomal involvement has been documented at the cytogenetic level: gains of chromosome 7 and losses of chromosome 10, 9p, 17p, and 22; further molecular characterization of these abnormalities has shown that mutational alterations of the p53 gene, together with the loss of alleles at 17p, seem to be the earliest abnormalities occurring during the genesis and progression of these neoplasms. The losses of regions on chromosomes 22 and 13 might also be relatively early events, perhaps characterizing subgroups of low grade gliomas. The mutations of the p53 gene in low grade tumors leads to a selective advantage in vivo and seems to be a critical step in the transformation from low grade to high grade gliomas. The loss of sequences on chromosome 10 and the deletions of 9p (that is loss of tumor suppressor genes on these locations), and epidermal growth factor receptor gene amplification, have been proposed as sequential abnormalities participating in glioblastoma tumorigenesis. The available data on meningiomas and neurinomas show that loss of regions on chromosome 22 is the main characteristic feature. Thus, tumor suppressor genes located in this chromosome are non-randomly involved in both neoplasms, and may present as solitary, sporadic tumors or as multiple associated lesions in neurofibromatosis type 2 (NF-2). The molecular analysis of a large series of meningiomas to determine the common chromosome 22 region lost has revealed that a putative meningioma tumor suppressor gene should be located at the distal 22q12.3-qter region. In parallel, the linkage data on the mapping of the NF-2 gene suggest that the NF-2 and meningioma loci are separate entities. However, some evidence exists on a possible participation of the NF-2 locus in the genesis of some meningiomas. The efforts to identify and isolate the genes involved, as well as their functional analysis, will contribute to a better understanding of the mechanisms of oncogenesis in these neoplasms and will doubtless have a clinical impact in the diagnosis, treatment and prognosis of nervous system tumors in patients.
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PMID:Cytogenetics and molecular genetics of nervous system tumors. 133 85

von Recklinghausen neurofibromatosis (NF1) is a common hereditary disorder characterized by neural crest-derived tumors, particularly benign neurofibromas whose malignant transformation to neurofibrosarcomas can be fatal. The NF1 gene has been mapped to a small region of chromosome 17q, but neither the nature of the primary defect nor the mechanisms involved in tumor progression are understood. We have tested whether NF1 might be caused by the inactivation of a tumor suppressor gene on 17q, analogous to that on chromosome 22 in NF2, by searching for deletions of chromosome 17 in NF1-derived tumor specimens. Both neurofibrosarcomas from patients with "atypical" NF and 5 of 6 neurofibrosarcomas from NF1 patients displayed loss of alleles for polymorphic DNA markers on chromosome 17. However, the common region of deletion was on 17p and did not include the NF1 region of 17q. Since no loss of markers on chromosome 17 was observed in any of 30 benign tumors from NF1 patients, the 17p deletions seen in neurofibrosarcomas are probably associated with tumor progression and/or malignancy. This region contains a candidate gene for tumor progression, p53, which has recently been implicated in the progression of a broad array of human cancers. In a preliminary search for p53 aberrations by direct sequencing of polymerase chain reaction-amplified DNA from 7 neurofibrosarcomas, 2 tumors that contained point mutations in exon 4 of the p53 gene were found, suggesting a role for this gene in at least some neurofibrosarcomas. Thus the formation of malignant neurofibrosarcomas may result from several independent genetic events including mutation of the NF1 gene, whose mechanism of tumorigenesis remains uncertain, and subsequent loss of a "tumor suppressor" gene on 17p, most likely p53.
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PMID:Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. 214 31

Malignant peripheral nerve sheath tumors (MPNST) are known to develop in patients with neurofibromatosis 1 (NF1), thus providing an excellent model for the study of multistep carcinogenesis in genetically predisposed individuals. To determine the sites of gene(s) involved in such a process, we have performed cytogenetic analysis on 10 tumors. The patients were five males and five females ranging in age from 15 to 77 years. Nine patients had NF1. Karyotypic analysis of these tumors exhibited complex clonal abnormalities of several chromosomes. Recurrent abnormalities (numerical as well as structural) of chromosomes 1, 11, 12, 14, 17, and 22 occurred in a substantial proportion of tumors studied. Although abnormalities of these chromosomes have been seen in a variety of other tumors, the aberrations of chromosomes 17 and 22 are of particular interest; chromosomes 17 and 22 carry the genes for NF1 and NF2, respectively. In addition to other clonal aberrations, six tumors had abnormalities of both chromosomes 17 and 22, while three tumors only had an abnormality of chromosome 17. In eight tumors a structural abnormality of chromosome 17 included deletion or a relative deficiency of 17p; in four of the tumors there was also either deletion or rearrangement of the NF1 locus at the cytogenetic level. One tumor had monosomy of chromosome 17. The abnormality of chromosome 22 was deletion of 22q11.2-->qter. This study suggests that the germline mutation in one of the copies accompanied by loss or inactivation of the second copy of the NF1 gene and tumor suppressor gene(s) on 17p and 22q may be associated with the neoplastic transformation; abnormalities of other chromosomes may be related to progression of MPNST. Although the role of the p53 gene in carcinogenesis is well documented in several tumor types, the role of the NF2 gene or other unidentified tumor suppressor gene(s) on chromosomes 22q, 1p, 11, 12, 14 remains to be seen.
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PMID:Cytogenetic analysis of soft tissue sarcomas. Recurrent chromosome abnormalities in malignant peripheral nerve sheath tumors (MPNST). 782 44

Neurological tumours are common neoplasms of both adults and children. Recent studies have begun to delineate the genetic abnormalities that underlie such tumours, and have implicated two classes of genes, oncogenes and tumour suppressor genes. Most investigations have focused on those astrocytomas that affect the cerebral hemispheres of adults, since these are the most common and malignant brain tumours. The high-grade astrocytomas that affect adults, such as glioblastoma multiforme, often have amplification of the epidermal growth factor receptor (EGFR) oncogene and loss of a variety of chromosomal loci that probably harbour tumour suppressor genes. Of the various tumour suppressor gene loci, the p53 gene on chromosome 17p has been studied most closely and has been shown to be mutated in both low- and high-grade astrocytomas. These genetic alterations may provide a means for subdividing astrocytomas into diagnostic categories. For instance, p53 gene mutations occur more commonly in glioblastomas from young adults and women, while EGFR gene amplification is more common in glioblastomas from older adults and men. For the other primary CNS tumours, genetic studies remain in their infancy. The neurocutaneous syndromes, such as neurofibromatosis types 1 and 2, have provided unique insights into neurological oncogenesis. The NF1 gene on chromosomes 17q and its product, neurofibromin, may be important in the formation of neurofibrosarcomas, while the NF2 gene on chromosome 22q and its product, merlin, are probably involved in the formation of schwannomas and other nervous system tumours. The further characterization of these and other neurological tumour genes will undoubtedly illuminate many other areas in neurooncology.
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PMID:Genetic basis of neurological tumours. 795 51

Identification of inherited cancer-predisposing genes offers opportunities for cancer prevention. Inherited susceptibility genes have been identified, primarily through studies of unusual cancer cases and families but also through general population studies. Examples include the RB1 gene for retinoblastoma; the WT1 gene for Wilms' tumor; germline p53 mutations in families with the Li-Fraumeni syndrome; the NF1 and NF2 genes for neuroblastomatosis, types 1 and 2; the VHL gene for renal cancer and other tumors associated with Von Hippel-Lindau disease; the APC gene for adenomatous polyposis coli; the BRCA1 gene for hereditary breast and ovarian cancer; and the mismatch repair genes for colon and other common cancers. For some cancers, identification of gene carriers might be beneficial for targeting screening and chemopreventive interventions. On the other hand, predisposition testing for cancer has the potential for harm from loss of insurability and employability, psychological distress, social stigmatization and other adverse effects. Research is needed to identify predisposition testing procedures that maximize benefits while minimizing harm to subjects. Chemoprevention trials in genetically susceptible populations offer the prospect of finding effective methods of reducing future cancer risk.
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PMID:Identification and management of inherited cancer susceptibility. 874 2

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.
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PMID:Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. 882 21

Ependymomas are glial tumors of the brain and spinal cord occurring both sporadically and in a familial syndrome, neurofibromatosis type 2 (NF2). Previous analyses performed on specimens obtained predominantly from adult patients have shown loss of DNA sequences from chromosome arm 22q, which is the location of the NF2 gene. Previously, we documented the consistent loss of chromosome arm 17p DNA in medulloblastoma and astrocytoma, which are the most common brain tumors in children. Although mutation of the TP53 gene located on 17p is the most frequent genetic mutation in all adult tumor types, such mutations are rare in most childhood brain tumors investigated to date. We studied a series of pediatric ependymoma specimens (16 intracranial and 2 spinal) for loss of 17p and 22q DNA sequences and for mutation of the TP53 and NF2 genes. None of the children had the clinical stigmata of NF2. We detected loss of 17p DNA sequences in 9 of the 18 specimens (50%); in 7 of 9 of these specimens (78%), the 144-D6 marker was deleted. In contrast, only 2 of these same 18 specimens (11%) showed loss of 22q DNA. One TP53 gene mutation was detected in a child from a cancer kindred. No mutations were detected in the NF2 gene. Our results suggest that loss of chromosome arm 17p DNA sequences is common in sporadic pediatric ependymomas and that, in contrast to ependymomas in adults, deletion of chromosome arm 22q sequences is rare. Furthermore, TP53 and NF2 gene mutations do not play an important role in the etiology of sporadic pediatric ependymomas.
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PMID:Molecular genetic analysis of chromosome arm 17p and chromosome arm 22q DNA sequences in sporadic pediatric ependymomas. 888 5

Though colorectal tumorigenesis has long been thought to be a multistep mechanisms, recently has it become possible to identify the molecular events that underlie the initiation and progression of colorectal carcinoma. Though the analysis of mutations in colorectal tumors at various stages of their development allows definition of a model for colorectal tumorigenesis, because the progression is the result of a series of genetic changes that accumulate activation of oncogene (K-ras), inactivation of tumor-suppressor gene (two-hit mutation of APC, Pla2s, p53, suppressor gene on chromosome 8p22 locus, NF2 and DCC) and mismatch repair gene (hMSH2, hMLH1 hPMS family and TGF beta II receptor linked DNA repair). These accumulation of genetic alterations contribute to tumor development and/or progression in primary colorectal carcinoma.
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PMID:[Genetic steps in colorectal cancer]. 892 Jun 76

Research on Neurofibromatosis (NF) has been directed at understanding what determines disease quiescence, exacerbation, and the possible malignant evolution. Studies on NF have examined the role of genetic oncosuppression in the evolution of the defence against the non-self. Paraffin fixed specimens of benign and malignant neoplasia, occurring in patients with NF1 and NF2, were tested for the presence of p53: a reliable marker of genetic oncosupression. The wild type variant of p53 is expressed in malignant neoplasia, and is usually not expressed in benign tumors. Contrariwise, an immune reaction it is seen in benign tumors and is practically absent in malignant tumors. Evidence of protein p53 in the various malignant neoplasias studied by our group seems to reflect the up-regulation on the oncosuppresive genetic potential that occurs while there is a lack of immunological defence. In the presence of an immunological defence, the expression p53 is normally not seen e.g. plexiform neurofibromas. The evolution of the various neoplastic types here reported was the same as that reported by current clinical and experimental models: the cell's defective genes are no longer suppressed and after activation the genes undergo initiation, promotion, and the cell sustains inflammatory-immune reactions that lead to fibrosis; what follows is a variable period of apparent quiescence. Severe pathogenic stimuli may act on predisposed cells and deteriorate pre-existing genetic damage, casting the cell into a phase of dysplastic or neoplastic proliferation that overcomes the body's defences. Hope for future therapy lies in the development of drugs that can either mimic the immune system or the proteins encoded by the oncosuppressor genes.
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PMID:Tumour suppressor genes, immunology and local manifestations of neurofibromatosis phenotypes. 900 79

Recent knowledge about biological role of tumor suppressor genes and their products: RB1, p53, WT1, DCC, APC/FAP, NF1, NF2, VHL, MCC and MTS1 is presented. The main approaches of these agents as physiological regulators of cell growth and proliferation are discussed. Views on the tumor suppressor genes involvement in the development of inherited and sporadic forms of cancer have been reviewed.
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PMID:[Antioncogenes--tumor suppression genes]. 933 80


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