Article (Scientific journals)
NFKBIA Deletion in Glioblastomas.
Bredel, M.; Scholtens, D. M.; Yadav, A. K. et al.
2011In New England Journal of Medicine
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Abstract :
[en] Background Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of kappa-light polypeptide gene enhancer in B-cells inhibitor-alpha), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR. 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Bredel, M.
Scholtens, D. M.
Yadav, A. K.
Alvarez, A. A.
Renfrow, J. J.
Chandler, J. P.
Yu, I. L.
Carro, M. S.
Dai, F.
Tagge, M. J.
Ferrarese, R.
Bredel, C.
Phillips, H. S.
Lukac, P. J.
Robe, Pierre ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine - Département des sciences biomédicales et précliniques
Weyerbrock, A.
Vogel, H.
Dubner, S.
Mobley, B.
He, X.
Scheck, A. C.
Sikic, B. I.
Aldape, K. D.
Chakravarti, A.
Harsh, G. R.
More authors (15 more) Less
Language :
English
Title :
NFKBIA Deletion in Glioblastomas.
Publication date :
2011
Journal title :
New England Journal of Medicine
ISSN :
0028-4793
eISSN :
1533-4406
Publisher :
Massachusetts Medical Society, Waltham, United States - Massachusetts
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 10 February 2011

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