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【NEJM】NFKBIA缺失的胶质母细胞瘤患者生存期较短
Bredel M, Scholtens DM, Yadav AK, Alvarez AA, Renfrow JJ, Chandler JP, Yu IL, Carro MS, Dai F, Tagge MJ, Ferrarese R, Bredel C, Phillips HS, Lukac PJ, Robe PA, Weyerbrock A, Vogel H, Dubner S, Mobley B, He X, Scheck AC, Sikic BI, Aldape KD, Chakravarti A, Harsh GR.
N Engl J Med. 2010 Dec 22. [Epub ahead of print]
http://www.nejm.org/doi/full/10.1056/NEJMoa1006312
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 κ-light polypeptide gene enhancer in B-cells inhibitor-α), 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-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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胶质母细胞瘤中NFKBIA缺失
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 κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR.
背景：表皮生长因子受体(EGFR)癌基因的扩增和活化突变是胶质母细胞瘤的分子标志。我们假想：EGFR信号通路的抑制剂之一NFKBIA（编码B细胞抑制子-α中的κ-光多肽基因增强子的核因子）的缺失，会促使无EGFR变化的胶质母细胞瘤的肿瘤生成。
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.
方法：我们分析了790例人类胶质母细胞瘤的NFKBIA和EGFR的缺失、突变或表达。我们研究了肿瘤细胞培养中NFKBIA的肿瘤抑制作用。我们将分子试验结果和570例相关胶质母细胞瘤患者结果进行了比较。
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-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease.
结果：胶质母细胞瘤中NFKBIA常缺失，但不突变；大多数突变发生在非经典亚型中。NFKBIA缺失和EGFR扩增呈不共存模式。NFKBIA表达的恢复降低了恶性表型，提高了NFKBIA缺失肿瘤细胞对化疗的敏感性；降低了EGFR扩增细胞的活力，但对NFKBIA和EGFR基因剂量均正常的细胞无类似作用。NFKBIA的缺失和低表达和不良结果相关。NFKBIA缺失肿瘤患者的结果与EGFR扩增肿瘤患者结果类似；和NFKBIA和EGFR基因剂量均正常的肿瘤患者相比，这些结果很差。基于NFKBIA和六氧甲基鸟嘌呤DNA甲基转移酶(MGMT)表达的双基因模型和胶质母细胞瘤的临床过程相关性极强。
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作者:admin@医学,生命科学 2011-01-06 11:02
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