Abstract 1789: NFKBIA deletion in malignant gliomas

Abstract

Abstract Introduction: Aberrant activation of the Epidermal Growth Factor Receptor (EGFR) oncoprotein is a molecular hallmark of glioblastomas. Two-thirds of tumors with excessive EGFR activation show alteration of the EGFR gene. The mechanism of deregulation of EGFR in the other third remains poorly understood. Nuclear factor of κB inhibitor alpha (NFKBIA) is a potential tumor suppressor. Methods: Multidimensional molecular profiles for NFKBIA and EGFR and clinical profiles of 732 malignant glioma patients from multiple academic institutions, The Cancer Genome Atlas Pilot Project, the Repository of Molecular Brain Neoplasia Data, and a randomized phase III trial of temozolomide. NFKBIA mutational and functional analyses in a glioblastoma cell model. Results: We found that about 25% of glioblastomas harbor heterozygous NFKBIA gene deletions at chromosome 14q13. NFKBIA functions as a haploinsufficient tumor suppressor in glioblastomas by terminating EGFR signaling. Tumors with NFKBIA deletion lacked EGFR amplifications, indicating functional redundancy of both genetic events in glioblastoma pathogenesis. Loss of NFKBIA gene dosage was significantly associated with briefer patient survival. Patients with low NFKBIA expression had a significantly worse outcome than patients with intact NFKBIA expression. NFKBIA expression was also significantly associated with patient survival in subsets of tumors with unmethylated promoter of the O6-methylguanine DNA methyltransferase (MGMT) gene. A combined outcome predictor model of NFKBIA and MGMT proved highly predictive of duration of survival. Conclusion: Deletion of NFKBIA is an alternative mechanism for tumorigenic increase in EGFR signaling in glioblastomas. NFKBIA inactivation is associated with shorter survival of patients with malignant gliomas. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1789.