December 22, 2010
BIRMINGHAM, Ala. - A University of Alabama at Birmingham study has identified a gene deletion in nearly 25 percent of all glioblastoma cases that is believed to be responsible for poor patient outcomes. The discovery could lead to better diagnosis and targeted treatments with drugs that are currently available.
Published online Dec. 22, 2010, in the New England Journal of Medicine, the study is the first to implicate the deletion of a copy of a gene called NFKBIA as a contributing cause of glioblastoma. Mutations in NFKBIA, normally present on chromosome 14 in two copies (one each on the maternally and paternally inherited copies), have been shown to be present in a number of cancers, including Hodgkin's lymphoma, multiple myeloma, melanoma and breast, lung, and colon cancer. This is the first study to associate a deletion of NFKBIA with human cancer.
The study's lead author and principal investigator Markus Bredel, M.D., Ph.D., associate professor in the UAB Department of Radiation Oncology and director of the UAB Radiation Oncology Brain Tumor Laboratory, said his team knew from earlier studies that as many as one- third of glioblastomas have an abnormality involving the gene coding for EGFR, a key cell-surface receptor for the hormone epidermal growth factor. However, they wanted to know what happened genetically in the other two-thirds.
"It's been known for 25 years that EGFR plays a role in glioblastoma as well as many other cancers, and that this gene is aberrantly activated in glioblastoma," said Bredel, also a scientist with the UAB Comprehensive Cancer Center. "We asked ourselves, what causes the majority of glioblastomas that don't have this defect?"
The investigators found NFKBIA deletions in one out of four of the 790 glioblastomas they studied. They also confirmed what had been found in earlier studies about EGFR, identifying abnormalities in that gene in about one-third of the samples. Interestingly, Bredel said, there were only a handful of instances where both gene abnormalities occurred in the same sample. They concluded that the two genetic defects, when combined, accounted for a majority of glioblastomas.
Bredel said that additionally, the team found that patients with either the NFKBIA or EGFR abnormality had a significantly shorter survival, despite maximal therapy, than patients whose tumors bore neither genetic defect.
"The discovery of the NFKBIA deletion's role in glioblastoma, and its dismal effect on survival, has important implications," Bredel said. "Our laboratory is currently trying to develop a robust method to screen patient samples for the gene defect."
In addition to prognostic implication, Bredel said the findings could also have an impact on treatment.
"Untreated, patients usually survive only few months after diagnosis. When surgically removed, tumors typically recur within six months. Radiation and temozolomide, a chemotherapy agent, can prolong survival, but not by much. These treatments extend median survival to perhaps 18 months," 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-kappa-B, NFKBIA's protein product," he said. "There are drugs approved for treatments of other cancers or currently under clinical investigation that may have that capacity."
In addition to his UAB faculty position, Bredel also holds a concurrent appointment as a professor of neuro-oncology, Department of Neurosurgery, Neurocenter and Comprehensive Cancer Center, University of Freiburg, Germany.
About the UAB Comprehensive Cancer Center
The UAB Comprehensive Cancer Center is among the 40 cancer centers in the nation to meet the stringent criteria for the National Cancer Institute's comprehensive designation. The center is a leader in groundbreaking research, reducing cancer disparities and leading-edge patient care.
About UAB
Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham (UAB) is the state of Alabama's largest employer and an internationally renowned research university and academic health center; its professional schools and specialty patient-care programs are consistently ranked among the nation's top 50. Find more information at www.uab.edu and www.uabmedicine.org.