Most Common Adult Brain Cancer Linked to Gene Deletion, Stanford Doctors Say
STANFORD, Calif. -- A study fast-tracked for online publication Dec. 22 in the New England Journal of Medicine has identified an important gene deletion in up to one of every four cases of glioblastoma, the most common adult brain cancer. This deletion contributes to tumor development, promotes resistance to therapy and considerably worsens a patient's survival prospects.
The deletion of the gene, known as NFKBIA, triggers biochemical processes similar to those resulting from a better-known aberration common in glioblastomas: alteration of the epidermal growth factor receptor, or EGFR. That both defects produce the same outcome may help explain why efforts to treat the disease by targeting only one aberration have faltered.
"Glioblastoma is the most malignant type of brain tumor," said Griffith Harsh, MD, professor of neurosurgery at the Stanford University School of Medicine and the study's senior author. Untreated, patients usually survive fewer than six months after diagnosis. After surgical excision, tumors often regrow rapidly. Radiation and temozolomide, a chemotherapeutic agent, can prolong survival, but not by much. These treatments extend median survival to perhaps 18 months.
Defects in NFKBIA, a gene normally present on chromosome 14, have been found in a wide range of cancers including Hodgkin's lymphoma, multiple myeloma, melanoma, and breast, lung and colon cancer. But the new study is the first to implicate the deletion of a copy of NFKBIA as a contributing cause of glioblastoma.
This discovery follows earlier findings that at least one-third of glioblastomas feature an abnormality of the gene coding for EGFR, the cell-surface receptor for the hormone known as epidermal growth factor. In such cases, EFGR is either present in excessive copies or is mutated in a manner that leaves the receptor stuck in the "on" position even when not stimulated by binding to the growth factor. Aberrant EGF receptors continuously send out biochemical signals that direct cells to proliferate, igniting tumor development.
"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 the study's principal investigator, Markus Bredel, MD, PhD, who is a visiting associate professor in Stanford's Department of Neurosurgery, associate professor at the University of Alabama-Birmingham and professor of neuro-oncology at the University of Freiburg in Germany. "We asked ourselves, what causes the majority of glioblastomas that don't have this defect?"
Bredel, Harsh and Branimir Sikic, MD, professor of oncology and clinical pharmacology at Stanford, had previously found that patients with low NFKBIA expression were resistant to temozolomide treatment. Based on that finding and on hints from other tumor types, Bredel, Harsh and their colleagues at Freiburg and Northwestern University (where most of the work was conducted under Bredel's direction) focused on NFKBIA.
"Glioblastoma is the most malignant type of brain tumor," said Griffith Harsh, MD, professor of neurosurgery at the Stanford University School of Medicine and the study's senior author. Untreated, patients usually survive fewer than six months after diagnosis. After surgical excision, tumors often regrow rapidly. Radiation and temozolomide, a chemotherapeutic agent, can prolong survival, but not by much. These treatments extend median survival to perhaps 18 months.
Defects in NFKBIA, a gene normally present on chromosome 14, have been found in a wide range of cancers including Hodgkin's lymphoma, multiple myeloma, melanoma, and breast, lung and colon cancer. But the new study is the first to implicate the deletion of a copy of NFKBIA as a contributing cause of glioblastoma.
This discovery follows earlier findings that at least one-third of glioblastomas feature an abnormality of the gene coding for EGFR, the cell-surface receptor for the hormone known as epidermal growth factor. In such cases, EFGR is either present in excessive copies or is mutated in a manner that leaves the receptor stuck in the "on" position even when not stimulated by binding to the growth factor. Aberrant EGF receptors continuously send out biochemical signals that direct cells to proliferate, igniting tumor development.
"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 the study's principal investigator, Markus Bredel, MD, PhD, who is a visiting associate professor in Stanford's Department of Neurosurgery, associate professor at the University of Alabama-Birmingham and professor of neuro-oncology at the University of Freiburg in Germany. "We asked ourselves, what causes the majority of glioblastomas that don't have this defect?"
Bredel, Harsh and Branimir Sikic, MD, professor of oncology and clinical pharmacology at Stanford, had previously found that patients with low NFKBIA expression were resistant to temozolomide treatment. Based on that finding and on hints from other tumor types, Bredel, Harsh and their colleagues at Freiburg and Northwestern University (where most of the work was conducted under Bredel's direction) focused on NFKBIA.
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