Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

Ishii, Nobuaki; Tada, Mitsuhiro; Hamou, M.-F.; Janzer, RC; Meagher‐Villemure, Kathleen; Od, Wiestler; Tribolet, Nicolas de; Meir, Erwin G. Van

doi:10.1038/sj.onc.1203241

Cited by 74 publications

(45 citation statements)

References 18 publications

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“…Knowledge derived from genetic syndromes (39) and GWAS studies (40,41) has shown that an inherited genetic component may accelerate this process. The fittest cell populations likely establish precancerous clones, although we have little direct evidence to support this process in human GBM because of limitations in detecting the early steps in brain cell transformation (42,43). Divergent genetic alterations in early transformed cells can subsequently give rise to a variety of clones under the selective pressure of the evolutionary ecosystem in the tumor (27)(28)(29)(35)(36)(37).…”

Section: Complexity Of Tumor Heterogeneity In Gbmmentioning

confidence: 99%

Overcoming therapeutic resistance in glioblastoma: the way forward

Osuka¹,

Meir²

2017

Journal of Clinical Investigation

394

311

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Section: Complexity Of Tumor Heterogeneity In Gbmmentioning

confidence: 99%

Overcoming therapeutic resistance in glioblastoma: the way forward

Osuka¹,

Meir²

2017

Journal of Clinical Investigation

394

311

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“…To further evaluate our hypothesis, we did the same set of transfections with another human glioblastoma cell line, LN229, which is PTEN (mutated in multiple cancers, phospha- (33). These cells showed a trend of NF-B activation similar to that observed in U87MG cells; however, the relative luciferase activity was reduced (Fig.…”

Section: Vol 24 2004 Role Of Shp-2 In Egfr-mediated Nf-b Activationmentioning

confidence: 99%

Distinct Domains in the SHP-2 Phosphatase Differentially Regulate Epidermal Growth Factor Receptor/NF-κB Activation through Gab1 in Glioblastoma Cells

Kapoor¹,

Zhan²,

Johnson

et al. 2004

Molecular and Cellular Biology

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The transcription factor nuclear factor B (NF-B) plays an important role in inflammation and cancer, is activated by a variety of stimuli including tumor necrosis factor alpha, interleukin-1, UV irradiation, and viruses, as well as receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR). Although previous studies suggest that EGFR can induce NF-B, the mechanism of this activation remains unknown. In this study, we identify the components of the EGFR-induced signalosome in human glioblastoma cells required to regulate NF-B activation. Immunoprecipitation analyses with ErbB-modulated cells indicate that association between SHP-2 and Grb2-associated binder 1 (Gab1) is the critical step in the formation of the signalosome linking EGFR to NF-B activation. We also show that EGFR-induced NF-B activation is mediated by the PI3-kinase/Akt activation loop. Overexpression of SHP-2, Gab1, and myristoylated Akt significantly upregulated NF-B transcriptional activity and DNA binding activity in glioblastoma cells. Interestingly, overexpression of either one of the two SH2 domain mutants of SHP-2, R32E or R138E, slightly reduced NF-B activity relative to that of wild-type SHP-2, indicating that the SH2 domains of SHP-2 are required for EGFR-induced NF-B activation. On the other hand, ectopic overexpression of either a Gab1 mutant incapable of binding to SHP-2 (Y627F) or a phosphatase-inactive SHP-2 mutant (C459S) caused a significant increase in NF-B activity. Moreover, SHP-2 C459S-expressing cells displayed higher Gab1 phosphotyrosine content, suggesting that SHP-2 regulates Gab1 phosphorylation through its phosphatase domain, which confers a negative regulatory effect on NF-B activity. These results indicate that SHP-2/Gab1 association is critical for linking EGFR to NF-B transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells and that SHP-2 acts as a dual regulator of NF-B activation.The epidermal growth factor receptor (EGFR) belongs to the ErbB family of type I receptor tyrosine kinases and has been implicated in tumorigenesis and neoplastic progression of many cancers, including breast, lung, and brain cancers. In brain cancer, particularly high-grade astrocytomas, also called glioblastoma multiforme (GBM), the majority of gene amplification events involve EGFR (6, 80), and it has been observed that EGFR is being amplified in ϳ50% of GBMs and a smaller percentage of anaplastic astrocytomas (80). The low frequency of amplification in anaplastic astrocytomas suggests that EGFR activation may be responsible for driving the transformation process towards GBM. The mouse models of glioma have supported these clinical observations (32). However, the specific signaling pathways involved in oncogenic transformation and cell growth induced by EGFR have not been completely characterized.The NF-B family of transcription factors, besides its role in inflammatory responses (3), has also been implicated in cell survival, transformation, and oncogenesis (4, 42). NF-B is confined to the cyt...

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“…However, the prognostic significance of p53 mutations in LGAs is unclear, with some studies showing it to be associated with malignant progression and shorter progressionfree and overall survival while others have not seen any significant association. 1,6,9,11,15,16 More recently, it has been shown that gemistocytic astrocytomas have a higher number of microglia, with more microglia being present when the fraction of gemistocytes is high. 8 Additionally gemistocytes were seen to be reactive for major histocompatibility complex Class II molecules.…”

mentioning

confidence: 99%

Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology

Babu

Bagley

Park

et al. 2013

JNS

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Object Low-grade astrocytomas are slow-growing, infiltrative gliomas that over time may progress into more malignant tumors. Various factors have been shown to affect the time to progression and overall survival including age, performance status, tumor size, and the extent of resection. However, more recently it has been suggested that histological subtypes (fibrillary, protoplasmic, and gemistocytic) may impact patient outcome. In this study the authors have performed a large comparative population-based analysis to examine the characteristics and survival of patients with the various subtypes of WHO Grade II astrocytomas. Methods Patients diagnosed with fibrillary, protoplasmic, and gemistocytic astrocytomas were identified through the Surveillance, Epidemiology, and End Results (SEER) database. The chi-square test and Student t-test were used to evaluate differences in patient and treatment characteristics between astrocytoma subtypes. Kaplan-Meier analysis was used to assess overall survival, and the log-rank test was used to evaluate the differences between survival curves. Univariate and multivariate analyses were also performed to determine the effect of various patient, tumor, and treatment variables on overall survival. Results A total of 500 cases were included in the analysis, consisting of 326 fibrillary (65.2%), 29 protoplasmic (5.8%), and 145 gemistocytic (29%) variants. Gemistocytic astrocytomas presented at a significantly older age than the fibrillary variant (46.8 vs 37.7 years, p < 0.0001), with protoplasmic and fibrillary subtypes having a similar age. Although protoplasmic and fibrillary variants underwent radiotherapy at similar rates, gemistocytic tumors more frequently received radiotherapy (p = 0.0001). Univariate analysis revealed older age, larger tumor size, and the use of radiotherapy to be poor prognostic factors, with resection being associated with improved survival. The gemistocytic subtype (hazard ratio [HR] 1.62 [95% CI 1.27–2.07], p = 0.0001) also resulted in significantly worse survival than fibrillary tumors. Bivariate analyses demonstrated that older age, the use of radiotherapy, and resection significantly influenced median survival. Tumor subtype also affected median survival; patients who harbored gemistocytic tumors experienced less than half the median survival of fibrillary and protoplasmic tumors (38 vs 82 months, p = 0.0003). Multivariate analysis revealed increasing age (HR 1.05 [95% CI 1.04–1.05], p < 0.0001), larger tumor size (HR 1.02 [95% CI 1.01–1.03], p = 0.0002), and the use of resection (HR 0.70 [95% CI 0.52–0.94], p = 0.018) to be independent predictors of survival. Examination of tumor subtype revealed that the gemistocytic variant (HR 1.30 [95% CI 0.98–1.74], p = 0.074) was associated with worse patient survival than fibrillary tumors, although this only approached significance. The protoplasmic subtype did not affect overall survival (p = 0.33). Conclusions Gemistocytic tumor histology was associated with worse survival than fibrillary and protoplasmic astrocytomas. As protoplasmic astrocytomas have a survival similar to fibrillary tumors, there may be limited utility to the identification of this rare variant. However, increased attention should be paid to the presence of gemistocytes in low-grade gliomas as this is associated with shorter time to progression, increased malignant transformation, and reduced overall survival.

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Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

Cited by 74 publications

References 18 publications

Overcoming therapeutic resistance in glioblastoma: the way forward

Overcoming therapeutic resistance in glioblastoma: the way forward

Distinct Domains in the SHP-2 Phosphatase Differentially Regulate Epidermal Growth Factor Receptor/NF-κB Activation through Gab1 in Glioblastoma Cells

Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology

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