Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

James, C. David; Galanis, Evanthia; Frederick, Lori; Kimmel, David W.; Cunningham, J. M.; Atherton-Skaff, Pamela; O’Fallon, Judith R.; Jenkins, Robert B.; Buckner, Jan C.; Hunter, Stephen B.; Olson, Jeanne; Scheithauer, Bernd W.

doi:10.3892/ijo.15.3.547

Cited by 36 publications

(33 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumor DNAs were examined for CDKN2A and PTEN homozygous deletion by multiplex PCR analysis as previously indicated (Liu et al, 1997;James et al, 1999). Samples yielding no detectable CDKN2A product or samples failing to show amplification of multiple PTEN exons were designated as having homozygous deletions of CDKN2A or PTEN, respectively.…”

Section: Cdkn2a and Pten Homozygous Deletion Analysismentioning

confidence: 99%

“…Preparatory polymerase chain reaction (PCR) was performed to provide a template for the sequence analysis of PTEN and TP53 mutations (all exons examined for PTEN and exons 5-8 examined for TP53; James et al, 1999). For each sequence analysis, a 10-l solution containing 10 -20 ng of PCR product from genomic DNA, as well as dNTPs, Taq polymerase, and buffer, was subjected to 30 cycles of cycle sequencing, with reaction products examined by electrophoresis through 6% denaturing acrylamide gels and exposure to X-ray film subsequent to gel drying.…”

Section: Pten and Tp53 Mutation Analysismentioning

confidence: 99%

“…A comparison of the incidence of these six genetic signature lesions in patient GBM tissues and established GBM cell lines revealed EGFR amplification as the only alteration that had a lower incidence in vitro (Filmus et al, 1985;Nister et al, 1988;He et al, 1994aHe et al, , 1994bTeng et al, 1997;Galanis et al, 1998;James et al, 1999). In fact, of the many GBM cell lines described in the literature, only the SKMG-3 GBM cell line has been shown to maintain a high-level EGFR copy number over time (Filmus et al, 1985;Thomas et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR

Pandita

Aldape

Zadeh

et al. 2003

Genes Chromosomes & Cancer

206

221

View full text Add to dashboard Cite

Despite the high incidence of EGFR amplification in patient glioblastoma multiforme (GBM) tissues, only a single GBM cell line, of the many described in the literature, is known to contain and maintain amplified EGFR. Because EGFR mutations in GBM manifest primarily, if not exclusively, in amplified form, it follows that the availability of cell lines with mutation of endogenous EGFR would also be in short supply. In fact, there are no GBM cell lines harboring the common EGFR mutants described in patient GBMs. These observations suggest that in vivo environments select for EGFR amplification, whereas in vitro environments, specifically cell cultures, select against this gene alteration. To contrast directly the fates of EGFR amplification in vivo and in vitro, as well as to examine potential relationships between EGFR amplification and mutation, we have established and maintained GBM explants as xenografts by serial passaging in nude mice. Analysis of EGFR copy number and EGFR mutation status in 11 patient tumors and their corresponding xenografts, as well as the monitoring of EGFR copy number during the establishment of a GBM cell line from a xenograft with amplified EGFR, indicated that selection for EGFR amplification is an in vivo phenomenon. Furthermore, our data indicated that EGFR mutation occurs only in tumors with EGFR amplification and showed that the selection of amplified mutant EGFR over amplified wild-type EGFR as a xenograft occurred rapidly and completely during tumor propagation.

show abstract

Section: Cdkn2a and Pten Homozygous Deletion Analysismentioning

confidence: 99%

Section: Pten and Tp53 Mutation Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR

Pandita

Aldape

Zadeh

et al. 2003

Genes Chromosomes & Cancer

206

221

View full text Add to dashboard Cite

show abstract

“…Attempts to correlate the genetic findings in AA with patient outcome have to-date not provided any convincing correlations with survival (Galanis et al, 1998;Olson et al, 1998;James et al, 1999;Smith et al, 2001;Rasheed et al, 2002).…”

mentioning

confidence: 99%

Mutations in Rb1 pathway-related genes are associated with poor prognosis in Anaplastic Astrocytomas

et al. 2005

View full text Add to dashboard Cite

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14 ARF and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P ¼ 0.009). This association was consistent in multivariate analysis, including adjustment for age (P ¼ 0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.

show abstract

“…High molecular weight DNAs isolated from flank tumor xenografts were used in preparatory PCRs to generate products for subsequent phosphatase and tensin homologue (PTEN) and TP53 sequence analysis (all exons examined for PTEN and exons 5-8 examined for TP53; ref. 24). Tumor homozygous PTEN deletion was determined based on lack of PTEN PCR product from preparatory PCRs.…”

mentioning

confidence: 99%

Use of an Orthotopic Xenograft Model for Assessing the Effect of Epidermal Growth Factor Receptor Amplification on Glioblastoma Radiation Response

Sarkaria

Carlson²,

Schroeder³

et al. 2006

Clinical Cancer Research

240

233

View full text Add to dashboard Cite

Purpose:The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFRamplified glioblastoma xenografts in an orthotopic athymic mouse model. Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days. Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser 473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone. Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.

show abstract

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

Cited by 36 publications

References 0 publications

Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR

Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR

Mutations in Rb1 pathway-related genes are associated with poor prognosis in Anaplastic Astrocytomas

Use of an Orthotopic Xenograft Model for Assessing the Effect of Epidermal Growth Factor Receptor Amplification on Glioblastoma Radiation Response

Contact Info

Product

Resources

About