Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary glioblastomas develop rapidly de novo through a genetic pathway characterized by amplification/overexpression of EGFR and of MDM2 genes. Secondary glioblastomas develop more slowly through progression from low grade or anaplastic astrocytoma and show a high incidence of a p53 mutation. In the present study, primary and secondary glioblastomas were analyzed for p16 deletions and CDK4 amplification by differential PCR and for loss of expression of the retinoblastoma (RB) gene by immunohistochemistry. Except for one case, alterations in the structure or expression of p16, CDK4 and RB were mutually exclusive. The overall incidence of aberrant expression of these genes coding for components of the cell-cycling-regulatory system was similar in primary (14/28; 50%) and secondary glioblastomas (9/23; 39%). However, p16 deletions were significantly more frequent in the former (10/28; 36%) than in the latter (1/23, 4%; P = 0.0075), suggesting that this alteration constitutes an additional genetic hallmark of the primary (de novo) glioblastoma.
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PMID:Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. 934 29

A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma.
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PMID:Biology and treatment of malignant glioma. 950 24

Glioblastomas may develop rapidly without clinical and histopathological evidence of a less malignant precursor lesion (de novo or primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas typically show overexpression of EGFR, but rarely p53 mutations, while secondary glioblastomas frequently carry a p53 mutation, but usually lack overexpression of EGFR, suggesting that these glioblastoma subtypes develop through distinct genetic pathways. In the present study, we assessed the expression of Fas/APO-1 (CD95), an apoptosis-mediating cell membrane protein, and its relation to necrosis phenotype in primary and secondary glioblastomas. Large areas of ischemic necroses were observed in all 18 primary glioblastomas, but were significantly less frequent in secondary glioblastomas (10 of 19, 53%; p = 0.0004). Fas expression was predominantly observed in glioma cells surrounding large areas of necrosis and was thus significantly more frequent in primary glioblastomas (18 of 18, 100%) than in secondary glioblastomas (4 of 19, 21%; p < 0.0001), suggesting that these clinically and genetically defined subtypes of glioblastoma differ in the extent and mechanism of necrogenesis. Necrosis and microvascular proliferation are histologic hallmarks of the glioblastoma. Following incubation of glioblastoma cell lines under hypoxic/anoxic conditions for 24-48 hours, Fas mRNA levels remained unchanged, whereas VEGF expression was markedly upregulated. This suggests that in contrast to VEGF Fas expression is not induced by ischemia/hypoxia. Analysis of Fas mRNA levels in a glioblastoma cell line containing a p53 mutation and an inducible wild-type p53 gene showed little difference under induced and noninduced conditions, suggesting that in glioblastomas, Fas expression is not directly linked to the p53 status.
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PMID:Necrogenesis and Fas/APO-1 (CD95) expression in primary (de novo) and secondary glioblastomas. 960 Feb 16

Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration associated with the evolution of malignant astrocytic tumors and it may involve several loci. The tumor suppressor gene PTEN (MMAC1) on chromosome 10q23 is mutated in approximately 30% of glioblastomas (WHO Grade IV). In this study, we assessed the frequency of PTEN mutations in primary glioblastomas, which developed clinically de novo, and in secondary glioblastomas, which evolved from low-grade (WHO Grade II) or anaplastic astrocytomas (WHO Grade III). Nine of 28 (32%) primary glioblastomas contained a PTEN mutation and an additional case showed a homozygous PTEN deletion. This indicates that after overexpression/amplification of the EGF receptor, loss of PTEN function is the most common alteration in primary glioblastomas. In this series, 5 of 28 (18%) primary glioblastomas showed both a PTEN mutation and EGFR amplification. In contrast, only 1 of 25 (4%) secondary glioblastomas contained a PTEN mutation, and none of them showed a homozygous PTEN deletion. The secondary glioblastoma with a PTEN mutation developed from an anaplastic astrocytoma that already carried the mutation. The observation that secondary glioblastomas have a p53 mutation as a genetic hallmark but rarely contain a PTEN mutation supports the concept that primary and secondary glioblastomas develop differently on a genetic level.
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PMID:PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. 969 Jun 72

Astrocytic tumors occasionally arise in the central nervous system following radiotherapy. It is not clear if these gliomas represent a unique molecular genetic subset. We identified nine cases in which an astrocytoma arose within ports of previous radiation therapy, with total doses ranging from 2400 to 5500 cGy. Irradiated primary lesions included craniopharyngioma, pituitary adenoma, Hodgkin's lymphoma, ependymoma, pineal neoplasm, rhabdomyosarcoma, and three cases of lymphoblastic malignancies. Patients ranged from 9 to 60 years of age and developed secondary tumors 5 to 23 years after radiotherapy. The 9 postradiation neoplasms presented as either anaplastic astrocytoma (3 cases) or glioblastoma multiforme (6 cases). Two of the latter contained malignant mesenchymal components. We performed DNA sequence analysis, differential polymerase chain reaction (PCR), and quantitative PCR on DNA from formalin-fixed, paraffin-embedded tumors to evaluate possible alterations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes. By quantitative PCR, we found EGFR gene amplification in 2 of 8 tumors. One of these demonstrated strong immunoreactivity for EGFR. Quantitative PCR showed chromosome 9p deletions including p16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7). Five of 9 tumors demonstrated diffuse nuclear immunoreactivity for p53 protein. Sequencing of the p53 gene in these 9 cases revealed a mutation in only one of these cases, a G-to-A substitution in codon 285 (exon 8). Somewhat unexpectedly, no mutations were identified in PTEN, a commonly altered tumor suppressor gene in de novo glioblastoma multiformes. Unlike some radiation-induced tumors, no activating point mutations of the K-ras proto-oncogene or base pair deletions of tumor suppressor genes were noted. These radiation-induced tumors are distinctive in their high histological grade at clinical presentation. The spectrum of molecular genetic alterations appears to be similar to that described in spontaneous high grade astrocytomas, especially those of the de novo type.
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PMID:Molecular genetic alterations in radiation-induced astrocytomas. 1032 96

Loss of heterozygosity on chromosome 10 (LOH#10) is the most frequent genetic alteration in glioblastomas and occurs in more than 80% of cases. We recently reported that PTEN (MMAC1) on 10q23.3 is mutated in approximately 30% of primary (de novo) glioblastomas but rarely in secondary glioblastomas that progressed from low-grade or anaplastic astrocytomas. Because secondary glioblastomas also show LOH#10, tumor suppressor genes other than PTEN are likely to be involved. We analyzed LOH on chromosomes 10 and 19, using polymorphic microsatellite markers in microdissected foci showing histologically an abrupt transition from low-grade or anaplastic astrocytoma to glioblastoma, suggestive of the emergence of a new tumor clone. When compared to the respective low-grade or anaplastic astrocytoma of the same biopsy, deletions were detected in 7 of 8 glioblastoma foci on 10q25-qter distal to D10S597, covering the DMBT1 and FGFR2 loci. Six of 8 foci showed LOH at one or two flanking markers of PTEN but did not contain PTEN mutations. LOH on 10p and 19q was found in only one case each. These data indicate that acquisition of a highly anaplastic glioblastoma phenotype with marked proliferative activity and lack of glial fibrillary acidic protein expression is associated with loss of a putative tumor suppressor gene on 10q25-qter.
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PMID:Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25-qter. 1043 32

Glioblastomas develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). There is increasing evidence that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR and MDM2 amplification/overexpression, PTEN mutations, and p16 deletions, whereas secondary glioblastomas frequently contain p53 mutations. Loss of heterozygosity (LOH) on chromosome 10 (LOH#10) is the most frequent genetic alteration in glioblastomas; the involvement of tumor suppressor genes, other than PTEN, has been suggested. We carried out deletion mappings on chromosome 10, using PCR-based microsatellite analysis. LOH#10 was detected at similar frequencies in primary (8/17; 47%) and secondary glioblastomas (7/13; 54%). The majority (88%) of primary glioblastomas with LOH#10 showed LOH at all informative markers, suggesting loss of the entire chromosome 10. In contrast, secondary glioblastomas with LOH#10 showed partial or complete loss of chromosome 10q but no loss of 10p. These results are in accordance with the view that LOH on 10q is a major factor in the evolution of glioblastoma multiform as the common phenotypic end point of both genetic pathways, whereas LOH on 10p is largely restricted to the primary (de novo) glioblastoma.
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PMID:Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. 1065 4

There are distinct genetic pathways leading to the glioblastoma, the most malignant astrocytic brain tumor. Primary (de novo) glioblastomas develop in older patients and are characterized by epidermal growth factor (EGF) receptor amplification/overexpression, p16 deletion, and PTEN mutations, whereas secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma develop in younger patients and frequently contain p53 mutations. In this study, we assessed the genetic profile of gliosarcoma, a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Single-strand conformation polymorphism followed by direct DNA sequencing revealed p53 mutations in five of 19 gliosarcomas (26%) and PTEN mutations in seven cases (37%). Homozygous p16 deletion was detected by differential polymerase chain reaction in seven (37%) gliosarcomas. The overall incidence of alterations in the Rb pathway (p16 deletion, CDK4 amplification, or loss of pRb immunoreactivity) was 53%, and these changes were mutually exclusive. Coamplification of CDK4 and MDM2 was detected in one gliosarcoma. None of the gliosarcomas showed amplification or overexpression of the EGF receptor. Thus gliosarcomas exhibit a genetic profile similar to that of primary (de novo) glioblastomas, except for the absence of EGFR amplification/overexpression. Identical PTEN mutations in the gliomatous and sarcomatous tumor components were found in two cases. Other biopsies contained p16 deletions, an identical p53 mutation, or coamplification of MDM2 and CDK4 in both tumor areas. This strongly supports the concept of a monoclonal origin of gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly malignant astrocytic neoplasm.
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PMID:Genetic profile of gliosarcomas. 1066 71

Glioblastomas develop rapidly de novo (primary glioblastomas) or slowly through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). Recent studies have shown that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR amplification/overexpression, PTEN mutation, homozygous p16 deletion, and loss of heterozygosity (LOH) on entire chromosome 10, whereas secondary glioblastomas frequently contain p53 mutations and show LOH on chromosome 10q. In this study, we analyzed LOH on chromosomes 19q, 1p, and 13q, using polymorphic microsatellite markers in 17 primary glioblastomas and in 13 secondary glioblastomas that progressed from low-grade astrocytomas. LOH on chromosome 19q was frequently found in secondary glioblastomas (7 of 13, 54%) but rarely detected in primary glioblastomas (1 of 17, 6%, p = 0.0094). The common deletion was 19q13.3 (between D19S219 and D19S902). These results suggest that tumor suppressor gene(s) located on chromosome 19q are frequently involved in the progression from low-grade astrocytoma to secondary glioblastoma, but do not play a major role in the evolution of primary glioblastomas. LOH on chromosome 1p was detected in 12% of primary and 15% of secondary glioblastomas. LOH on 13q was detected in 12% of primary and in 38% of secondary glioblastomas and typically included the RB locus. Except for 1 case, LOH 13q and 19q were mutually exclusive.
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PMID:Loss of heterozygosity on chromosome 19 in secondary glioblastomas. 1085 Aug 66

Because of the absence of specific marker, the histological classification of gliomas remain controversial. Identifying the genetic alterations involved in gliomas makes it possible to define specific molecular pathway of tumoral progression and to define markers of prognostic and diagnostic relevance. For example, p53 mutations are frequent in low grade astrocytoma, anaplastic astrocytoma and secondary glioblastoma suggesting that it takes place at an early stage of development of astrocytic tumors, whereas inactivation of PTEN arises mainly in glioblastomas and EGFR amplification is preferentially associated with "de novo" glioblastoma. Loss of chromosomes 1p and 19q characterizes oligodendroglial tumors. However the putative tumor suppressor genes located on 1p and 19q and specifically inactivated are not known yet. Emerging technologies, like microarrays and microdissection, will allow to refine molecular data and provide a molecular classification of gliomas mechanism involved in the repair of the respiratory epithelium.
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PMID:[Genes implicated in glial tumors]. 1104 99


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