Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the p53 gene have been recognized in brain tumors, and clonal expansion of p53 mutant cells has been shown to be associated with glioma progression. However, studies on the p53 gene have been limited by the need for frozen tissues. We have developed a method utilizing polymerase chain reaction (PCR) for the direct analysis of p53 mutation by single-strand conformation polymorphism (SSCP) and by direct DNA sequencing of the p53 gene using a single 10-microns paraffin-embedded tissue section. We applied this method to screen for p53 gene mutations in exons 5-8 in human gliomas utilizing paraffin-embedded tissues. Twenty paraffin blocks containing tumor were selected from surgical specimens from 17 different adult patients. Tumors included six anaplastic astrocytomas (AAs), nine glioblastomas (GBs), and two mixed malignant gliomas (MMGs). The tissue section on the stained glass slide was used to guide microdissection of an unstained adjacent tissue section to ensure > 90% of the tumor cell population for p53 mutational analysis. Simultaneously, microdissection of the tissue was also carried out to obtain normal tissue from adjacent areas as a control. Mutations in the p53 gene were identified in 3 of 17 (18%) patients by PCR-SSCP analysis and subsequently confirmed by PCR-based DNA sequencing. Mutations in exon 5 resulting in amino acid substitution were found in one thalamic AA (codon 158, CGC > CTT: Arg > Leu) and one cerebral hemispheric GB (codon 151, CCG > CTG: Pro > Leu).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of p53 gene mutations in human gliomas by polymerase chain reaction-based single-strand conformation polymorphism and DNA sequencing. 816 51

The effects of regional heterogeneity on the accuracy of histological grading of gliomas are well known, but little has been reported about its implications for other diagnostic modalities. This study investigated the relationships of regional heterogeneity in tumor proliferative activity, measured by Ki-67 labeling indices (LI), and histological grades for 16 regionally sampled glioma resections. There was a strong correlation between histological grades and Ki-67 LI in individual regions (p < 0.001), and both methods demonstrated comparable heterogeneity. Heterogeneity increased with tumor grade, probably as an expression of the increased genetic instability that accompanies tumor progression. Similarly, regions with comparable proliferative activity tended to cluster, paralleling clonal expansion. Thus, both histological grading and Ki-67 LI are subject to heterogeneity-induced sampling errors that limit their diagnostic accuracy, particularly in small biopsies. However, fewer grading errors occurred when using both methods together than when using either method alone, suggesting that the use of multiple techniques may reduce the adverse effects of regional heterogeneity on diagnostic accuracy. Regional heterogeneity appears to be a ubiquitous feature of gliomas: it also has been reported in karyotype, p53 oncogene mutations, and PDGF and EGFR expression. The effects of regional heterogeneity on new methods for studying gliomas need to be considered.
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PMID:Regional heterogeneity in the proliferative activity of human gliomas as measured by the Ki-67 labeling index. 822 80

Using polymerase chain reaction-single strand polymorphism(PCR-SSCP) and nucleotide analyses, p53 gene mutation was examined in 13 pontine gliomas many of which were of juvenile onset. A total of 15 mutations were detected in 8 cases, of which 5 revealed multiple or tandem mutations. The mutations included 6 G:C-A:T and 4 A:T-G:C transitions and 4 G:C-T:A and 1 A:T-T:A transversions. There was only 1 transition at the CpG site. Normal tissues of the same patients revealed no mutation, suggesting that these mutations were somatic, but not of germ line, in nature. The pattern of mutation characterized by frequent multiple or tandem occurrence, predominancy of transition at non-CpG sites and relatively frequent transversions suggested that pontine glioma might be related with some mutagenic or carcinogenic agents.
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PMID:p53 gene mutations in pontine gliomas of juvenile onset. 824 Mar 61

Mutations in, and aberrant expression of, the p53 tumor suppressor gene were assessed in 17 cell lines derived from human malignant brain tumors (glioblastoma multiforme). Exons 5 through 8 were screened by single strand conformational polymorphism analysis (SSCP), followed by direct DNA sequencing. Mutations were found in 6 of 17 glioma cell lines, i.e., at a frequency similar to that found in primary malignant gliomas. Loss of the wild type allele was observed in 4 of the mutated cell lines. Two cell lines had the same mutation (CGG-->TGG; Arg-->Trp) in codon 248. Five of 6 mutations were transitions, 4 of which occurred at CpG dinucleotides. In one cell line a 10-bp deletion at the intron 4/exon 5 junction was found. Five of 6 glioma cell lines contained a mutation identical to that in the respective primary tumor despite prolonged in vitro culture (140-221 passages). Thus, the acquisition of p53 mutations during culture appears to be infrequent. Two cell lines derived from heterozygous tumors maintained the wild type p53 allele during long term culture. p53 protein levels were assessed by immunofluorescence cytochemistry and immunoprecipitation followed by Western blot analysis and revealed elevated levels of the p53 protein, although to a variable extent, in all cell lines with p53 mutations. A marked p53 protein accumulation was also observed in two cell lines lacking p53 mutations in exons 5 through 8, indicating that a prolonged half life of the gene product is not solely dependent on an aberrant coding sequence. The remaining cell lines had either low levels or no detectable p53 protein; one of the latter contained a gross rearrangement of the p53 gene. Our results suggest that with respect to p53 gene status, glioma cell lines usually resemble the original tumors and may, therefore, be suitable for studying the biological changes associated with p53 mutations in glial tumors.
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PMID:p53 protein accumulation and gene mutations in human glioma cell lines. 825 36

Inherited mutations of the p53 and neurofibromin genes are thought to cause two distinct neoplastic disorders in which gliomas occur, the Li-Fraumeni syndrome and neurofibromatosis type 1. We investigated the possibility that inherited mutations in specific regions of these genes also contributed to the clustering of gliomas in otherwise normal families. Twenty-six members of 16 families with glioma were screened for germline mutations of exons 5 through 9 of the p53 gene and exon 24 of the neurofibromin gene using a polymerase chain reaction-single-strand conformation polymorphism method. No germline mutations were found, suggesting that the genetic basis of familial glioma is distinct from that of gliomas occurring in the Li-Fraumeni syndrome, and that inherited mutations of the catalytic domain of neurofibromin do not predispose affected glioma families to these tumors.
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PMID:Absence of hereditary mutations in exons 5 through 9 of the p53 gene and exon 24 of the neurofibromin gene in families with glioma. 828 83

Chromosome 17p has been shown to be an early and frequent target for loss of heterozygosity through mitotic recombination in astrocytomas. These losses are frequently accompanied by point mutations in the p53 gene of the remaining allele, resulting in loss of wild type p53 function. However, a fraction of astrocytomas retain constitutional heterozygosity and do not have p53 mutations; some of these lose wild type p53 activity through binding to the protein product of amplified mdm2 genes. To test whether loss of wild type p53 biological function is a necessary step in astrocytoma progression we analyzed p53 expression and biological function in 13 glioma cell lines. All the cell lines expressed a 2.8-kilobase p53 transcript and showed various amounts of p53 protein by immunoprecipitation, except for cell line LN-Z308 which had only a small truncated p53 mRNA and no protein expression. To test whether the p53 expressed in these cell lines was functionally wild type or mutant we transfected them with a plasmid construct harboring a chloramphenicol acetyltransferase (CAT) reporter gene under the control of transcriptional elements that are induced by wild type but not mutant p53. Four lines were shown to retain wild type p53 function. Sequencing of the p53 gene in two of these cell lines confirmed the wild type genotype. These results show that inactivation of the p53 gene is not an obligatory step in glioblastoma genesis. This suggests either that two pathways (p53 inactivation dependent or independent) may lead to a tumor group classified histologically as glioblastoma or that in some cases p53 mutations are bypassed due to the presence of mutations in downstream effector genes.
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PMID:Analysis of the p53 gene and its expression in human glioblastoma cells. 830 26

The development of a malignant tumor generally entails a series of events that damage the genome of a somatic cell and result in the malignant phenotype. These events chronicle the malignant progression of a tumor; a dynamic process in which more aggressive and growth-deregulated cell populations are constantly evolving. Gliomas, the most common primary tumors of brain, are known to become increasingly malignant with time. Within recent years, several details of the molecular genetic events associated in their progression have been determined. The earliest events of glioma progression include loss of genetic information from the long arms of chromosomes 13 or 22, or the short arm of chromosome 17 for which targeting of the TP53 (p53) gene has been indicated. Loss of a single complement of type I interferon (IFN) genes from 9p and loss of genetic information from 19q are seen in the tumors of intermediate malignancy grade. Events associated with the most malignant of glial tumors include loss of the second, type I IFN gene complement, loss of genetic information from chromosome 10, and gene amplification (most commonly the epidermal growth factor receptor, in 40% of cases). These findings have helped elucidate the events associated with glial tumorigenesis, and through the identification of specific genes, have provided a starting point for investigating the molecular biology of central nervous system neoplasia.
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PMID:Gene and chromosomal alterations associated with the development of human gliomas. 834 89

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.
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PMID:Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene. 843 70

The incidence of primary brain tumors has increased dramatically among elderly North Americans during the past two decades. Numerous chromosomal abnormalities have been associated with these tumors; various subsets of these abnormalities are specific to certain types of brain tumors. Astrocytic gliomas may exhibit losses of genetic information from chromosomes 9p, 10q, 11p, 13q, 17p, or 22. Mutations of the p53 gene are found mostly in the malignant astrocytic forms and have been linked to malignant tumor transformation and progression. Functional and structural abnormalities of the neurofibromatosis 1 (NF1) gene and overexpression of the epidermal growth factor receptor have been associated with expression of the malignant glioma phenotype. Other less clearly defined abnormalities in astrocytomas include mutations of the retinoblastoma (RB) gene and overexpression of platelet-derived growth factor; transforming growth factor-alpha and -beta; the c-erb B-1, c-myc, ras, c-fos, and ros oncogenes; and insulin-like growth factor I and II. In other glioma tumors, p53 mutations are either infrequent, as in oligodendrogliomas, or absent, as in ependymomas. Occasionally, medulloblastomas exhibit p53 mutations and loss of genetic information from chromosomes 6q and 16q or expression of the c-erb B-2 oncogene. Loss of heterozygosity in chromosome 22 is the most frequent event in meningiomas, suggesting the presence of a tumor-suppressor gene in this chromosome.
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PMID:Epidemiology, cytogenetics, and molecular biology of brain tumors. 849 8

Increasing the susceptibility of tumor cells to apoptotic cell death following chemotherapy is of importance to the outcome of cancer treatment. Although the tumor suppressor gene p53 is required for efficient induction of apoptosis by chemotherapeutic agents, it is not the only apoptosis mediator gene. The molecular mechanisms mediating apoptosis following chemotherapy via p53-dependent or p53-independent pathways remain unclear. We show here that cis-diamminedichloroplatinum (cisplatin) induces the expression of interleukin-1 beta-converting enzyme (ICE), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, in murine and human malignant glioma cells during apoptosis regardless of their p53 status. Furthermore, overexpression of the murine ICE gene induces apoptosis in these tumor cells. The apoptosis induced by cisplatin treatment or murine ICE overexpression can be suppressed by the tetrapeptide ICE inhibitor Ac-YVAD-CMK or the apoptosis inhibitors bcl-2 or bcl-2-related bcl-XL gene. These findings suggest that ICE may mediate apoptosis induced by chemotherapy, and its induction could represent a novel approach for the effective treatment of malignant glioma.
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PMID:Interleukin-1 beta-converting enzyme mediates cisplatin-induced apoptosis in malignant glioma cells. 852 9


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