Glioblastoma multiforme (GBM) is a biologically complex tumor with alterations in numerous signaling pathways.1,9 One pathway in particular, involving the epidermal growth factor receptor (EGFR), is mutated in the majority of GBMs.12,13 The EGFR pathway normally activates the transcription factor of κ-light polypeptide gene enhancer in B-cells (NF-κB). To this end, NF-κB inhibitor-α (NFKBIA) repress NF-κB and signaling in the NF-κB and EGFR pathways.5,6 Interestingly, recent investigations have identified NF-κB mutations to exist in GBMs and other oncologic lesions.7–10
To further elucidate this relationship, Bredel et al studied 790 GBMs for deletions, mutations, or overexpression of NFKBIA and EGFR.7 More specifically, the authors analyzed the tumor-suppressor activity of NFKBIA in tumor-cell culture and compared the molecular results with clinical outcomes. The authors found heterozygous NFKBIA deletions in approximately 25% of lesions. They also found that deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. In cells cultured from tumors with NFKBIA deletion, restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy. This also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Patients who had tumors with NFKBIA deletion had similarly poor outcomes as compared to patients with tumors harboring EGFR amplification, which were significantly worse than those without either alteration.
Of note, the authors found 33% to 45% of glioblastomas have a methylated MGMT promoter, which silences expression of the corresponding MGMT mRNA transcription and provides a more favorable response to temozolomide and radiation therapy.11,12 To account for this, Bredel et al stratified patient risk status, according to NFKBIA and MGMT expression, into high-risk (low NFKBIA and high MGMT expression), low-risk (high NFKBIA and low MGMT expression), and one intermediate-risk (either low NFKBIA and low MGMT expression or high NFKBIA and high MGMT expression).7 The estimated median survival in the low-risk, intermediate-risk, and high-risk groups was 92 weeks, 59 weeks, and 44 weeks, respectively. In addition, the association between risk and survival was even more pronounced in the case of patients with newly diagnosed tumors treated with adjuvant radiotherapy and temozolomide.
These findings have significant implications for tumor classification. Work from the Cancer Genome Atlas project has identified 4 glioma subtypes: neural, proneural, mesenchymal, and classical.3 When the distribution of these 2 mutations is segregated according to tumor subtype EGFR alterations tend to occur in the classical group, as opposed to the NFKBIA deletion which falls into the three non-classical subtypes. It is possible, however, that both mutations may cause NF-kB activation as a general GBM feature regardless of subtype. To clarify, future studies may provide a greater understanding of the unique characteristics exhibited by these glioma subtypes.
Moving forward, further in vitro and in vivo studies are necessary to more clearly determine how NFKBIA deletion affects the NF-kB pathway. Assessment of NF-kB activity in tumors with NFKBIA deletion and EGFR amplification may help reveal if these mutations produce similar phenotypes. Moreover, studies regarding the downstream effects of NF-kB and EGFR alterations will help determine their ultimate phenotypical expression. Most importantly, the documented high rate of NFKBIA and EGFR mutations in GBMs, along with their similar biology and significant impact on survival, should lead investigators to develop novel, targeted, and individualized therapeutic regimens that are tailored to patient specific genotypes.