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

A predisposition to the development of certain specific and familial cancers is associated with the inheritance of a single mutated gene. In the best-characterized cases, this primary mutation is a loss of function mutation consistent with viability but resulting in neoplastic change consequent to the acquisition of a second somatic mutation at the same locus. Such genes are referred to as tumor-suppressor genes. Classical examples are the Rb-1 gene associated with the development of retinoblastoma and the p53 gene, which is associated with a wider range of neoplasms, including breast cancer. Other tumor-suppressor genes have been isolated which are associated with Wilms' tumor, neurofibromatosis, and inherited and sporadic forms of colorectal cancer. Some of these genes appear to act as negative regulators of mitotic cycle genes, and others may have different properties. The nature of these genes is discussed, as is the evidence for the involvement of tumor-suppressor genes in other inherited, and sporadic, forms of cancer. Some recent data on the Wilms' tumor gene, WT1, and on the involvement of the p53 gene in breast cancer are presented, and the importance of genomic imprinting in contributing to the excess of suppressor gene mutations in chromosomes of paternal origin is considered.
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PMID:Tumor-suppressor genes: cardinal factors in inherited predisposition to human cancers. 133 26

Malignant schwannomas are soft-tissue neoplasms that occur at increased frequency with germline alterations of the neurofibromatosis-1 (NF1) gene at 17q11.2. We report molecular and cytogenetic characterization of a malignant schwannoma cell line established from an individual affected with NF1. This cell line has a complex hyperdiploid karyotype with two cytogenetically identical der(13)t(13;17)(p11,q11.2) chromosomes. Using somatic cell hybrids, we mapped twelve chromosome-17 probes to either the der(13)t(13;17) chromosome or a small der(17) chromosome. Two chromosome-17p loci, including the p53 tumor suppressor gene, were present in the schwannoma cell line, but did not map to either of these chromosomes. Loss of heterozygosity studies indicated that the two der(13)t(13;17) chromosomes arose by duplication, presumably after the translocation event. The 17q11.2 translocation break-point maps distal to the NF1 gene, and may not disrupt its functioning. Although NF1 mRNA was detected in this cell line by polymerase chain reaction, Northern blot analysis revealed very little or none of the 13-kb mature NF1 transcript. This suggests that the single remaining allele of the NF1 gene contains a mutation that results in either greatly reduced transcription or message instability.
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PMID:Molecular characterization of a 17q11.2 translocation in a malignant schwannoma cell line. 148 4

In the past year we have witnessed significant progress in understanding the molecular basis of cancerogenesis and in identifying the genetic determinants of susceptibility to cancer. In particular, the finding that the same tumor suppressor genes play a pathogenic role in both the inherited and the sporadic forms of some childhood tumors has suggested that this gene class may also be involved in adult tumors derived from inherited familial cancer syndromes. The identification of the gene defect underlying the Li-Fraumeni syndrome, a germline mutation of the tumor suppressor gene p53, has fully confirmed that suggestion. Three other genes associated with the inherited cancer syndromes neurofibromatosis type I (NF-1) and familial adenomatous polyposis have been cloned and partially characterized. In addition to these genes, which have a relatively high penetrance and contribute directly to tumorigenesis, other genes that lead to cancer as a secondary effect seem to act in determining an individual's overall cancer risk. The latter genes are most likely related to defective processes of DNA repair or to regulation of carcinogen metabolism. In this context the analysis of models of murine strains with different genetic susceptibility to cancer of various organs may be a useful tool for unveiling the genetic basis for cancer susceptibility in individuals.
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PMID:Genetics and cancer. 159 Dec 84

Previous emphasis in cancer research has been placed on genes in which activating mutations are found in experimental systems and sometimes in human tumors, and many of these genes are the cellular homologs of retroviral oncogenes. Studies of genes whose functions are necessary for maintenance of the normal cellular state, but for which loss-of-function mutations lead to tumor development, are limited. The latter genes have been variously termed 'tumor suppressor genes', 'recessive oncogenes', and 'anti-oncogenes', and each term defines a specific aspect of their properties and may not always be applicable. The retinoblastoma (RB) gene is the first such gene to be identified, and was isolated based on its chromosome localization and on the recessive nature of the tumor phenotype. That is, both wild type RB alleles must be inactivated in a single cell for neoplastic transformation to occur, and deletions at the chromosomal locus now known to contain RB are often found in retinoblastoma cells. Candidate genes for Wilms' tumor and neurofibromatosis type I have also been identified recently, and loss of function of these genes seems to be indicated for these diseases. Allelic loss of chromosome 17p13 is frequently observed in many tumor types. The p53 gene was mapped to this chromosomal region and has been shown to be a tumor suppressor gene, and germ-line mutations of p53 recently were found to be correlated with Li-Fraumeni syndrome, a syndrome characterized by multiple neoplasms. Rapid progress in studies of tumor suppressor genes points to diverse mechanisms for their functioning in the negative regulation of cell growth. A scenario depicting cell growth control by positive and negative regulators, based on new and emerging findings, is the main focus of this review.
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PMID:Tumor suppressor genes: a new era for molecular genetic studies of cancer. 175 64

Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder mapped to 17q11.2 and typically characterized by the occurrence of neural crest-derived tumors. The gene has recently been cloned using reverse genetics or "positional cloning" approaches. Its function, however, remains unknown. We have performed cytogenetic and molecular analyses on 9 malignant tumors from NF1 patients to look for loss of alleles or chromosome rearrangements involving chromosome 17 to test the hypothesis that the NF1 gene acts as a recessive "tumor suppressor" gene. Loss of alleles on this chromosome was detected for 3 of 9 malignant tumors. Two peripheral nerve sheath tumors showed allele loss at informative loci on both the long and short arms of chromosome 17. In contrast, a glioblastoma with focal gliosarcoma showed loss of heterozygosity on the short arm of chromosome 17 only, and not at loci on the long arm. One nerve sheath tumor was previously shown by direct sequence analysis to have a point mutation at the TP53 locus at 17p13. These data support a role for the TP53 gene or other genes on the short arm of chromosome 17 in at least some malignancies in NF1. Six other neurofibrosarcomas showed no allele loss at informative loci on chromosome 17. Cytogenetic analysis was performed on 7 tumors, including 2 with allele loss. The two tumors with allele loss showed abnormal karyotypes while all others were normal. Southern blot and pulsed-field gel analysis using probes within or closely linked to the NF1 locus detected no gross deletions or rearrangements in the tumors studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis. 190 41

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

Neurofibromatosis type I (NFI) is a common autosomal dominant disorder with an increased risk for developing benign and malignant tumors. The NFI gene has been cloned and maps to 17q11.2, and the gene product acts as a tumor suppressor gene. Here we analyzed the role of mutations in TP53 in four malignant NFI tumors. Mutations were found in 3 out of 4 tumors. One of these mutations is a common missense mutation in codon 278 in one of the previously identified hot spots for mutations. The two other are hitherto unreported mutations, including a splice mutation of exon 3 and a nonsense mutation in exon 4. In addition, these four tumors also showed loss of heterozygosity (LOH) for markers on chromosome 17 in the region of TP53. Malignant NFI tumors are initiated by a somatic inactivation of the second NFI allele. Tumor progression, however, occurs by accumulation of additional genetic abnormalities, such as homozygous inactivation of TP53, as demonstrated in this paper.
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PMID:TP53 mutations are frequent in malignant NF1 tumors. 752 38

The familial occurrence of gliomas, in the absence of well-defined neurological tumor syndromes such as the neurofibromatoses, is uncommon. We present a family of ten children in which the four eldest suffered from gliomas. Three of these siblings had histologically verified glioblastoma multiforme, and one patient also had an intestinal non-Hodgkin's lymphoma, but there were no stigmata or family history of a neurological tumor syndrome. Cytogenetic studies of the proband revealed a normal karyotype. Molecular genetic analysis of the proband's glioblastoma revealed two mutations in the p53 tumor suppressor gene, but these were not present in the germline DNA, mutations were not detected in the MTS1 gene in the tumors or in the germline DNA. These findings suggest that a genetic factor may be responsible for the clustering of glial tumors in this family, but it is unlikely that the genetic alteration is mutation of the p53 gene. The data are discussed in light of the literature on familial brain tumors.
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PMID:Glioblastoma multiforme in four siblings: a cytogenetic and molecular genetic study. 759 55

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

Work in the field of molecular neuro-oncology has evolved from a purely descriptive catalogue of regional mutations to the implication of specific genes in the malignant process. Reverse genetic strategies have resulted in the cloning of the neurofibromatosis-1 and neurofibromatosis-2 genes, the molecular physiology of the p53 gene, and work is in progress toward identifying specific genes in each of the other major genomic regions in which genetic events accumulate during malignant progression in human gliomas. Current studies are examining the functional role of genes implicated in glioma malignancy and investigating the mechanisms of their dysregulation in the generation of the malignant phenotype.
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PMID:Recent advances in brain tumor molecular biology. 808 Aug 50


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