Missing Gene: A Cause for Common Brain Cancer? | Medical News and Health Information

Missing Gene: A Cause for Common Brain Cancer?

(Ivanhoe Newswire) -- The deletion of a gene called NFKBIA may cause glioblastoma, the most common and malignant brain cancer. Researchers at the Stanford University School of Medicine recently discovered that the deletion of this gene, which is known to promote tumor development and resistance to therapy, was present in one out of every four glioblastoma cases.

When NFKBIA is deleted, certain biochemical processes occur with striking similarity to an onset of glioblastoma, which often results in an alteration of the epidermal growth factor receptor (EGFR). At least one-third of glioblastomas are associated with gene-coding abnormalities for EGFR, which include an excess of duplicate copies or a mutation that causes the receptor to constantly be "on," even when it is not stimulated by outside factors. This aberration is part of why glioblastoma is so malignant, as it causes tumors to quickly spread and even rapidly regenerate after surgical removal. Survival can be prolonged by chemotherapy and radiation but usually by only an average of 18 months.

"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," lead investigator and visiting associate professor at Stanford, associate professor at the University of Alabama-Birmingham and neuro-oncology professor at Germany’s University of Freiburg, Markus Bredel, M.D., Ph.D., was quoted as saying. "We asked ourselves, what causes the majority of glioblastomas that don’t have this defect?"

The researchers had previously discovered that cancer patients with low NFKBIA expression were resistant to chemotherapeutic temozolomide treatments. This finding, as well as information gathered from other types of tumors, led the researchers to further research NFKBIA.

NFKBIA problems have been linked to many cancers such as Hodgkin’s lymphoma, multiple myeloma, and melanoma as well as breast, colon and lung cancer but have not been linked to glioblastoma until now.

The researchers took hundreds of tumor samples from glioblastoma patients who had been treated at various clinics between the years of 1989 and 2009. Out of all of these samples, NFKBIA deletions were found in a whopping 25 percent. Their findings regarding EGFR were also confirmed by the study, as EGFR gene aberrations were present in one-third of the samples. It was rare that both of these genetic defects were present in one patient’s tumor, but taken together, they constituted a majority of all glioblastomas observed. Patients whose tumors had either one of the defects had a lower survival rate, even after extensive therapy, compared to patients whose tumors did not have genetic defects.

NFKBIA and EGFR defects also affect a molecule called NF-kappa-B, which is a "transcription factor" present in all cells. In cancer cells, NF-kappa-B can stimulate proliferation and a resistance to natural cell death and are often activated by biochemical signals transmitted by overworking or mass-produced EGFR. This NF-kappa-B stimulation causes cancer cells to resist temozolomide treatments.

NFKBIA works differently. When deleted, it interrupts a binding process between NF-kappa-B and an NF-kappa-B inhibiting protein called I-kappa-B, thus allowing it to move into the nucleus and alter gene expression. This causes NF-kappa-B to act in the same exact manner as seen with EGFR.

The researchers made their discoveries after growing glioblastoma cells and testing them with various methods to stimulate the activity of I-kappa-B in the cells. When cells with EGFR hyperactivity or NFKBIA deletion were tested, normal cell behavior and appearance was achieved, and the cells were thus less likely to resist temozolomide.

"If we can determine that a patient’s glioblastoma has the NFKBIA deletion, we can target that tumor for treatment with drugs that stabilize I-kappa-B, NFKBIA’s protein product," Bredel was quoted as saying. The researchers are currently working to find an inexpensive, quick and dependable method to identify NFKBIA deletion.

Source: Stanford University Medical Center
Missing Gene: A Cause for Common Brain Cancer? | Medical News and Health Information