December 30, 2010 — Deletion of a gene whose product inhibits the epidermal growth factor receptor (EGFR)-signaling pathway appears to cause tumorigenesis in patients with glioblastoma who lack the excessive EGFR activation that characterizes many glioblastomas, according to a study published online December 22 in the New England Journal of Medicine.
Involving cancer researchers at several US and European institutions, the investigation found that the effects of deleting NFKBIA (nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α) resemble the effects of amplifying EGFR. Both genetic alterations are linked to shorter survival in glioblastoma patients. A major function of the NFKBIA protein is to inhibit NF-κB, a regulator of DNA transcription, by forming a complex with it.
Among human brain tumors, glioblastoma multiforme is the most common and most lethal, making up more than 50% of primary brain tumors in adults. About 10,000 new cases occur in the United States annually. Very few glioblastoma patients live more than 3 years, and the prognosis has barely changed in the past 20 years.
This study analyzed genetic changes in NFKBIA and EGFR in 790 glioblastomas from patients treated from 1989 to 2009; tumor-cell cultures were also used to investigate NFKBIA activity as a tumor suppressor. The results of these laboratory investigations were compared with clinical outcomes in 570 patients with glioblastoma.
Deletion of NFKBIA occurred often in glioblastomas, although usually in "nonclassical subtypes of the disease." Interestingly, NFKBIA deletion and EGFR amplification rarely occur together.
"We think that both alterations lead to the same biochemical events in glioblastoma cells; namely, increased EGFR signaling and EGFR-mediated activation of NF-κB," said first author Markus Bredel, MD, PhD, via email to Medscape Medical News. "These 2 alterations likely compensate for each other in glioblastomas (genetic compensation). This is probably why glioblastomas usually show only 1 alteration and do not need to acquire the second alteration."
Dr. Bredel is associate professor in the departments of Radiation Oncology, Genetics, and Cell Biology, and the UAB Comprehensive Cancer Center, and he directs the Radiation Oncology Brain Tumor Laboratory, University of Alabama at Birmingham School of Medicine. He is also affiliated with the University of Freiburg, Germany; Stanford University, California; and Northwestern University in Chicago, Illinois.
Patients with glioblastoma in the present research were in 10 study sets, based on the institutional source of the tissue and data; study sets ranged in size from 15 to 219 patients. In study set 1, for instance, 24.2% of the 219 patients had a heterozygous deletion involving NFKBIA. In study set 2, 20.3% of the 182 tumors had fewer than 1.5 copies of NFKBIA. Similar proportions of heterozygous deletions of NFKBIA were identified in study sets 3 (n = 46) and 4 (n = 36).
Interestingly, when coding and/or promoter regions of NFKBIA were sequenced in study sets 5 and 6, no mutations were found, leading to the conclusion that decreased NFKBIA function in glioblastomas is typically a result of reduced copy number.
"The traditional view [regarding tumor suppressor genes]...was that both alleles (ie, maternal and paternal copies) of a tumor suppressor gene need to be inactivated so that a tumor suppressor cannot function anymore," explained Dr. Bredel. "For example, 1 of the 2 alleles could be mutated, and the other 1 could be lost (deleted). However, it is now becoming increasingly evident that deletions in tumor suppressor genes that affect only 1 of the 2 copies can also have relevance in cancer."
Tumor-suppressor genes of that type are called haploinsufficient. Haploinsufficiency occurs when a cell with 2 copies of each chromosome only has a single functioning copy of a certain gene. With too little gene product produced, the cell is unable to function normally. A tumor-suppressor gene is considered haploinsufficient if inactivation of only 1 allele leads to tumorigenesis, although the remaining wild-type allele is still functional.
"We think that NFKBIA could be a haploinsufficient tumor-suppressor gene in glioblastomas, as we found that 1 of the 2 alleles is deleted in about 25% of the tumors; however, the second allele does not carry any inactivating mutations," Dr. Bredel said.
Patients with NFKBIA deletion but no EGFR amplification did not differ significantly from patients with EGFR amplification but normal NFKBIA in terms of survival (hazard ratio for death, 1.13; 95% confidence interval, 0.72 - 1.79; P = .57). However, patients whose tumors contain either NFKBIA deletion or EGFR amplification had shorter survival after diagnosis compared with patients with normal expression levels of both genes (hazard ratio for death with NFKBIA deletion, 1.69 [P = .02]; hazard ratio for death with EGFR amplification, 1.48 [P = .04]).
Asked about the clinical value of this enhanced understanding of glioblastoma, Dr. Bredel said: "If we can determine that a patient's glioblastoma harbors the NFKBIA deletion, we can potentially target that tumor for treatment with drugs capable of stabilizing levels of I-κ-B-α, NFKBIA's protein product. There are actually drugs approved for treatment of other cancers, or currently under clinical investigation, that may have that capacity. For example, bortezomib (Velcade; Takeda Pharmaceutical Company) is...approved in the United States for treating relapsed multiple myeloma and mantle cell lymphoma."
Medscape Medical News received commentary from Albert S. Baldwin, PhD, associate director of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, and president of TheraLogics, Inc, also based in Chapel Hill. The company is developing IKK inhibitors, which inhibit the kinase that is critical in activating NF-κB.
"One could consider gene therapy using [the NFKBIA protein]. There are groups using viruses to target glioma, so this is a possibility," Dr. Baldwin said via email. "The loss of [the NFKBIA protein] suggests that the NF-κB pathway (for which NFKBIA is a negative regulator) is functional in glioma. So blocking NF-κB, through inhibitors of the kinase that controls NF-κB, is a possibility. IKK inhibitors are under development and study."
Dr. Bredel has disclosed no relevant financial relationships. Dr. Baldwin is the founder and president of TheraLogics, Inc, a company developing IKK inhibitors.
N Engl J Med. Published online December 22, 2010.
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Cite this: NFKBIA Deletion, EGFR Amplification Have Similar Effects on Glioblastoma Outcome - Medscape - Dec 30, 2010.
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