Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using restriction fragment length polymorphism (RFLP) analysis, we demonstrated in 4 of 20 patients with astrocytomas loss of heterozygosity on the short arm of chromosome 17 (17p), in the telomeric segment distal to DNA marker pEW301 (locus D17S58). The loss of heterozygosity may uncover a mutation in a tumour suppressor gene and thus lead to or permit tumour formation. The p53 tumour suppressor gene, which is localized at 17p13, is a likely candidate for the tumour suppressor gene involved. Of the 4 patients with loss of heterozygosity on 17p, one patient had a grade I astrocytoma, another patient had a grade II astrocytoma and 2 patients had glioblastoma multiforme. Since the loss of heterozygosity on 17p was detected in low-grade as well as in high-grade astrocytomas, it is possible that p53 suppressor gene loss may be an early genetic event in the multistep process of astrocytoma formation.
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PMID:Loss of heterozygosity on the short arm of chromosome 17 in human astrocytomas. 135 Dec 57

Inactivation of tumour suppressor genes or anti-oncogenes as well as activation of dominant acting oncogenes seem to be important mechanisms in the pathogenesis of gliomas. We compared constitutional and tumoural genotypes at different restriction fragment length polymorphism loci (RFLP) on chromosomes 10 and 17 in 15 unrelated individuals. Loss of heterozygosity (LOH) pointing to chromosomal loss or deletions was detected for at least one chromosome 17 marker in 11 gliomas (astrocytomas grades I-III and glioblastoma multiforme), whereas LOH for chromosome 10 loci was only detected in 3 out of 9 cases of glioblastoma multiforme and was not detected in low grade gliomas. Since LOH for chromosome 10 loci seems to be restricted only to glioblastoma multiforme, it is possible that recessive mutations on chromosome 10 are engaged in tumour progression from astrocytomas to glioblastoma multiforme. As LOH of chromosome 17 markers occurs in astrocytomas as in glioblastoma multiforme, chromosome 17 loci probably are involved in early tumour development.
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PMID:Loss of constitutional heterozygosity in human astrocytomas. 135 19

We have examined a series of 13 benign and 27 malignant human gliomas for evidence of molecular abnormalities of proto-oncogene and putative tumour suppressor gene loci. The results indicated that specific molecular lesions were associated with increasing grades of malignancy. Thus, loss of genetic material on chromosome 17 was present with approximately equal frequency in both benign and malignant gliomas, whereas loss of loci on chromosome 10 was seen only in malignant gliomas. Only the most malignant tumours, known as glioblastoma multiforme, had more than one molecular abnormality in the same tumour. These findings may contribute to our understanding of glial tumour development, as well as improve the accuracy of tumour diagnosis.
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PMID:Multiple sequential molecular abnormalities in the evolution of human gliomas. 167 78

Among tumours of the nervous system, mutations of the p53 tumour suppressor gene are largely restricted to neoplasms of astrocytic origin. These are the most common human brain tumours and span a wide range of biologic behavior, from the slowly growing low-grade astrocytoma (WHO Grade II) to anaplastic astrocytoma (WHO Grade III) and, ultimately, the glioblastoma multiforme (WHO Grade IV). In low grade astrocytomas, p53 mutations with or without loss of heterozygosity on chromosome 17p are the principle detectable change. Anaplastic astrocytomas contain p53 mutations in approximately one third of cases and further display loss of heterozygosity on chromosome 19q and homozygous loss of 9p21, tentatively identified as multiple tumour suppressor 1 (MTS-1). In addition to these genetic alterations, glioblastomas show loss of chromosome 10 and amplification of the EGF receptor gene at an incidence of > 60% and > 40%, respectively. The type and distribution of p53 mutations are not suggestive of specific environmental carcinogens operative in their etiology.
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PMID:Genetic alterations associated with glioma progression. 753 15

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

We analysed for loss of alleles on chromosome 10, 25 astrocytomas, 3 ependymomas, 2 medulloblastomas, 2 juvenile pilocytic astrocytomas, 2 gangliogliomas, 1 subependymal giant cell astrocytoma and 1 anaplastic oligoastrocytoma. A battery of 12 DNA markers spanning chromosome 10 was employed. Loss of heterozygosity on chromosome 10 was seen in 16 tumours (13 glioblastoma multiforme, 2 anaplastic astrocytomas, and 1 anaplastic oligoastrocytoma), but not in any of the low-grade astrocytomas examined. High-resolution restriction fragment length polymorphism (RFLP) analysis showed that the loss of alleles in a number of tumours involved two separate large regions of chromosome 10 (10p-proximal 10q and distal 10q). However, a small common region of deletion overlap could not be identified. Our data indicate that the loss of alleles on chromosome 10 is a common finding, seen in over two-thirds of malignant astrocytomas, and may be suggestive of the presence of two or more chromosome 10 tumour suppressor genes involved in astrocytoma formation. Nevertheless, the possibility of these genetic changes being secondary and not causative of the deregulated cell growth cannot be excluded. Regardless of the mechanisms involved, however, chromosome 10 deletions may be a genetic marker for malignant astrocytomas.
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PMID:Loss of heterozygosity for alleles on chromosome 10 in human brain tumours. 809 56

Neoplastic transformation occurs in all glial cell types of the human nervous system, producing a wide variety of clinico-pathological entities and morphological variants. Astrocytomas are most common and span an unusually wide spectrum, ranging from the slowly growing juvenile pilocytic astrocytoma to the highly malignant glioblastoma multiforme. Diffusely infiltrating astrocytomas of the cerebral hemispheres show an inherent tendency for progression towards a more malignant phenotype. This change is morphologically categorized in histologic grading schemes (e.g., WHO Grade II to IV) and is associated with the sequential acquisition of genetic alterations, including mutations in the p53 and homozygous deletions of the p16 tumour suppressor genes. Loss of heterozygosity on chromosomes 10 and 19q as well as amplification of the EGF receptor are largely restricted to malignant gliomas and thus considered late events in astrocytoma progression. Gliomas often show phenotypic expression of different glial cell lineages (e.g., oligoastrocytoma). Recent studies suggest that the occurrence of mixed gliomas is not indicative of a polyclonal origin but rather reflects altered gene expression, leading to a change in the balance of growth factors influencing glioma differentiation.
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PMID:Histopathology, classification, and grading of gliomas. 858 58

Our understanding of the complexity of genetic abnormalities involved in the tumourigenesis of malignant gliomas is as yet rudimentary. However, we can discern distinctive patterns of loss of genetic material and amplification of chromosomal regions that characterize both the different types of gliomas as well as the different malignancy grades. In this review, we discuss through specific examples of recent work on astrocytomas and glioblastoma multiforme, the importance of several tumour suppressor genes and oncogenes in the development of these glial tumours. In conclusion it would seem that distinct genetic changes in different genes, the protein products of which interact in particular growth control mechanism may lead to the same cellular abnormality. It seems likely that many further genetic abnormalities affecting genes coding for proteins, either involved in the cellular mechanisms yet identified or in new growth control mechanisms. Will be found in the near future.
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PMID:Molecular pathogenesis of astrocytoma and glioblastoma multiforme. 926 50

Amongst the human astrocytic tumours, the commonest of primary brain tumours, the clinical outcome of astrocytoma (AS) is significantly better than anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Often, low grade tumours can progress to or recur with a more malignant phenotype. Recent loss of heterozygosity (LOH) reports suspect the involvement of a tumour suppressor gene, different from p53, in the 17p13.3 region of the human chromosome. However, the effect of LOH of 17p13.3 region on tumour histology at presentation and prognosis is as yet undefined. As a first step to define the role of this putative oncogene in astrocytic tumour progression, we correlated the LOH of a locus, D17S379, in 17p13.3 region and the p53 locus in 17p13.1 region with the histopathology of astrocytic tumours by PCR based microsatellite and restriction fragment length polymorphism of DNA extracted from microdissected paraffin sections of 45 astrocytic tumours of different histopathological grades. LOH of D17S379 was significantly associated (P=0.02) with AA and GBM (high grade malignancy), while no such preferential association was found with LOH of p53. There were no mutations in the exons 5 to 9 of p53 gene in the five tumours with LOH of D17S379 but not of p53 region. In a case of AA with a heterogenous microscopic appearance, heterozygosity of D17S379 was lost only in the area with a more malignant histology while both areas had no LOH or mutation of p53. A locus at the 17p13.3 region, independent of the p53 locus, is involved in a large subset of astrocytic tumours during transformation into a more malignant phenotype, and thus may be a link in the chain of genetic events occurring in astrocytic tumour progression.
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PMID:Loss of heterozygosity of a locus on 17p13.3, independent of p53, is associated with higher grades of astrocytic tumours. 926 74

The human polyomavirus, JCV, is the causative agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal human demyelinating disease. PML results from the cytolytic destruction of oligodendrocytes, the myelin-producing cells of the nervous system. JCV has also been shown to be tumorigenic in several animal models. Transgenic mice expressing the JCV early protein, T-antigen, develop poorly differentiated neural crest origin tumours. Intracerebral inoculation of JCV into newborn hamsters induces medulloblastomas, astrocytomas, and primitive neuroectodermal tumours. Further, inoculation of the virus into the brains of non-human primates, owl and squirrel monkeys, results in astrocytomas and glioblastoma multiforme. Several case reports have associated JCV with human CNS tumours in patients with concomitant PML, and one such report has detected JCV in a glial tumour in the absence of PML. The induction of neural origin tumours by JCV has been studied in transgenic mice harbouring the early genome of the virus. Alterations in the level and function of tumour suppressor proteins p53 and Rb, as well as associated cell cycle regulators, have been detected in tumour tissue from JCV T-antigen transgenic mice. Possible mechanisms by which JCV may exert its oncogenic potential by alteration of cellular growth control pathways in both humans and experimental animals are discussed.
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PMID:Oncogenic potential of human neurotropic papovavirus, JCV, in CNS. 977 30


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