Abstract | BACKGROUND: METHODS: We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons. RESULTS: NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease. CONCLUSIONS: Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.
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Authors | Markus Bredel, Denise M Scholtens, Ajay K Yadav, Angel A Alvarez, Jaclyn J Renfrow, James P Chandler, Irene L Y Yu, Maria S Carro, Fangping Dai, Michael J Tagge, Roberto Ferrarese, Claudia Bredel, Heidi S Phillips, Paul J Lukac, Pierre A Robe, Astrid Weyerbrock, Hannes Vogel, Steven Dubner, Bret Mobley, Xiaolin He, Adrienne C Scheck, Branimir I Sikic, Kenneth D Aldape, Arnab Chakravarti, Griffith R Harsh 4th |
Journal | The New England journal of medicine
(N Engl J Med)
Vol. 364
Issue 7
Pg. 627-37
(Feb 17 2011)
ISSN: 1533-4406 [Electronic] United States |
PMID | 21175304
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- I-kappa B Proteins
- NFKBIA protein, human
- NF-KappaB Inhibitor alpha
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Topics |
- DNA Mutational Analysis
- Gene Amplification
- Gene Deletion
- Gene Expression
- Genes, erbB-1
- Glioblastoma
(genetics, mortality)
- Humans
- I-kappa B Proteins
(genetics)
- Kaplan-Meier Estimate
- NF-KappaB Inhibitor alpha
- Prognosis
- Tumor Cells, Cultured
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