Comparative Study of p53 Gene and Protein Alterations in Human Astrocytic Tumors

Louis, David N.; Deimling, Andreas von; Chung, Richard; Rubio, Mari-Paz; Whaley, Jean M.; Eibl, Robert H.; Ohgaki, Hideaki; Wiestler, Otmar D.; Thor, Ann D.; Seizinger, Bernd R.

doi:10.1097/00005072-199301000-00005

Cited by 209 publications

(102 citation statements)

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“…This mutation has been documented by single-strand conformational polymorphism study, 21,22,26,29 immunohistochemistry, 13,15,18,30 and yeast functional assays. 28,31 The aim of the current study was to categorize gliomas genetically to promote the development of evidence based cancer therapies.…”

Section: Discussionmentioning

confidence: 98%

“…12 Secondary GBMs are characterized by functional loss of TP53 mainly caused by the gene mutations 13,14 and partial or complete loss of chromosome 10q. 12 As the p53 gene mutation has been shown to occur in the early stage of progression to secondary GBM, 14,[15][16][17][18][19] it can presumably be present in astrocytic tumors of different stages. Whether the mutation affects sensitivity to therapy and prognosis remains controversial.…”

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confidence: 99%

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Influence of p53 mutations on prognosis of patients with glioblastoma

Shiraishi¹,

Tada²,

Nakamura³

et al. 2002

Cancer

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BACKGROUNDThe influence of p53 mutations on the biology of astrocytic tumors is controversial. p53 is thought to be inactivated in the early stage of gliomagenesis; however, what role its inactivation plays in the malignancy of gliomas remains unknown. To understand the significance of p53 inactivation, the authors identified the locus of p53 gene mutation in glioma samples at different stages of progression and studied the correlation between the mutation and clinical behavior.METHODSSamples from newly diagnosed gliomas, including pure and mixed astrocytomas, were analyzed for p53 mutations using a yeast functional assay. To determine the locus of the gene mutations, DNA sequencing was performed.RESULTSThe incidence of p53 mutations was higher in anaplastic astrocytomas (AA, 48%) than glioblastomas (GBM, 31%). There was no significant difference in the average ages of GBM patients with and without p53 mutations (54.9 years ± 2.3 and 53.2 years ± 4.6, respectively). In GBM patients, the mutation did not affect progression free survival or overall survival. Astrocytomas and GBM differed in the distribution of p53 mutation loci.CONCLUSIONSThe p53 gene mutation does not markedly affect the survival of GBM patients. The difference in the location of p53 mutations between AA and GBM suggests that in gliomas, the p53 mutation may contribute not only to tumorigenesis (as an early event) but also to progression to malignancy (as a late event). Cancer 2002;95:249–57. © 2002 American Cancer Society.DOI 10.1002/cncr.10677

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

Influence of p53 mutations on prognosis of patients with glioblastoma

Shiraishi¹,

Tada²,

Nakamura³

et al. 2002

Cancer

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“…p53 gene mutation and p53 protein accumulation have been documented in low-and high-grade astrocytomas, and it has been suggested that p53 mutation occurs in the initial stages of tumour formation (Ellison et al, 1992; Deimling et al, 1992Louis et al, 1993). This is in keeping with the demonstration that loss of heterozygosity for loci on the short arm of chromosome 17 (17p) (where the p53 gene is located) is shared by cells in each malignancy stage (ElAzouzi et al, 1989;James et al, 1989James et al, , 1990Bigner & Vogelstein, 1990;Venter & Thomas, 1991;Cavenee, 1992;von Diemling et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

p53 protein in low-grade astrocytomas: a study with long-term follow-up

Iuzzolino¹,

Ghimenton²,

Nicolato³

et al. 1994

Br J Cancer

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“…Alteration of its function can also lead to genomic instability, which is thought to be an early event in glioma oncogenesis. 3 Normal p53 function is important in the cellular response to genotoxic agents causing DNA damage. The p53 protein acts as a transcription factor, inducing growth arrest by modulating specific downstream target genes, including p21, which arrests cells in late G 1 by inhibiting cyclin-dependent kinase activity, 4,5 or by up-regulating GADD45, which inhibits DNA synthesis and may activate nucleotide excision repair.…”

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Combined radiation and p53 gene therapy of malignant glioma cells

et al. 1999

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More than half of malignant gliomas reportedly have alterations in the p53 tumor suppressor gene. Because p53 plays a key role in the cellular response to DNA-damaging agents, we investigated the role of p53 gene therapy before ionizing radiation in cultured human glioma cells containing normal or mutated p53. Three established human glioma cell lines expressing the wild-type (U87 MG, p53 wt ) or mutant (A172 and U373 MG, p53 mut ) p53 gene were transduced by recombinant adenoviral vectors bearing human p53 (Adp53) and Escherichia coli ␤-galactosidase genes (AdLacZ, control virus) before radiation (0 -20 Gy). Changes in p53, p21, and Bax expression were studied by Western immunoblotting, whereas cell cycle alterations and apoptosis were investigated by flow cytometry and nuclear staining. Survival was assessed by clonogenic assays. Within 48 hours of Adp53 exposure, all three cell lines demonstrated p53 expression at a viral multiplicity of infection of 100. p21, which is a p53-inducible downstream effector gene, was overexpressed, and cells were arrested in the G 1 phase. Bax expression, which is thought to play a role in p53-induced apoptosis, did not change with either radiation or Adp53. Apoptosis and survival after p53 gene therapy varied. U87 MG (p53 wt ) cells showed minimal apoptosis after Adp53, irradiation, or combined treatments. U373 MG (p53 mut ) cells underwent massive apoptosis and died within 48 hours of Adp53 treatment, independent of irradiation. Surprisingly, A172 (p53 mut ) cells demonstrated minimal apoptosis after Adp53 exposure; however, unlike U373 MG cells, apoptosis increased with radiation dose. Survival of all three cell lines was reduced dramatically after Ͼ10 Gy. Although Adp53 transduction significantly reduced the survival of U373 MG cells and inhibited A172 growth, it had no effect on the U87 MG cell line. Transduction with AdLacZ did not affect apoptosis or cell cycle progression and only minimally affected survival in all cell lines. We conclude that responses to p53 gene therapy are variable among gliomas and most likely depend upon both cellular p53 status and as yet ill-defined downstream pathways involving activation of cell cycle regulatory and apoptotic genes.

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Comparative Study of p53 Gene and Protein Alterations in Human Astrocytic Tumors

Cited by 209 publications

References 0 publications

Influence of p53 mutations on prognosis of patients with glioblastoma

Influence of p53 mutations on prognosis of patients with glioblastoma

p53 protein in low-grade astrocytomas: a study with long-term follow-up

Combined radiation and p53 gene therapy of malignant glioma cells

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