- p53: Mutations in p53, a tumor suppressor gene, were among the first genetic alterations identified in astrocytic brain tumors. The p53 gene appears to be deleted or altered in approximately 25-40% of all glioblastoma multiformes, more commonly in secondary glioblastoma multiformes. The p53 immunoreactivity also appears to be associated with tumors that arise in younger patients.
- Epidermal growth factor receptor (EGFR) gene: The EGFR gene is involved in the control of cell proliferation. Multiple genetic mutations are apparent, including both over expression of the receptor as well as re-arrangements that result in truncated isoforms. However, all the clinically relevant mutations appear to contain the same phenotype leading to increased activity. These tumors typically show a simultaneous loss of chromosome 10 but rarely a concurrent p53 mutation. Overexpression or activation mutations in this gene are more common in primary glioblastoma, with mutations appearing in 40-50% of these tumors. One such common variant, EGFR VIII, has shown promise as a target for kinase inhibitors, immunotoxins, and peptide vaccines.
- MDM2: Amplification or overexpression of MDM2 constitutes an alternative mechanism to escape from p53-regulated control of cell growth by binding to p53 and blunting its activity. Overexpression of MDM2 is the second most common gene mutation in glioblastoma multiformes and is observed in 10-15% of patients. Some studies show that this mutation has been associated with a poor prognosis.
- Platelet-derived growth factor-alpha (PDGF-alpha) gene: The PDGF gene acts as a major mitogen for glial cells by binding to the PDGF receptor (PDGFR). Amplification or overexpression of PDGFR is typical (60%) in the pathway leading to secondary glioblastomas.
- PTEN: PTEN (also known as MMAC and TEP1) encodes a tyrosine phosphatase located at band 10q23.3. The function of PTEN as a cellular phosphatase, turning off signaling pathways, is consistent with possible tumor-suppression action. When phosphatase activity is lost because of genetic mutation, signaling pathways can become activated constitutively, resulting in aberrant proliferation. PTEN mutations have been found in as many as 30% of glioblastomas, more commonly in primary glioblastoma multiformes.
- MAGE-E1 - A glioma-specific member of the MAGE family that is expressed at up to 15-fold higher levels in glioblastoma multiformes than in normal astrocytes.
- NRP/B - A nuclear-restricted protein/brain, which is expressed in neurons but not in astrocytes (NRP/B mutants are found in glioblastoma cells.)
- Additional genetic alterations in primary glioblastomas include p16 deletions (30-40%), p16INK4A, and retinoblastoma (RB) gene protein alterations. Progression of secondary glioblastomas often includes LOH at chromosome arm 19q (50%), RB protein alterations (25%), PTEN mutations (5%), deleted-in-colorectal-carcinoma gene (DCC) gene loss of expression (50%), and LOH at 10q.
- Extensive cell phone use.
- Head injury, N-nitroso compounds, occupational hazards, electromagnetic field exposure (inconclusive).
- Lumbar puncture (generally contraindicated but occasionally necessary for ruling out lymphoma).
- Patients older than 70 years: Less aggressive therapy is sometimes considered, using radiation or temozolomide alone.
- Interstitial brachytherapy is of limited use and is rarely used.
- Radiosensitizers, such as newer chemotherapeutic agents, targeted molecular agents, and antiangiogenic agents may increase the therapeutic effect of radiotherapy.
- Other therapy modalities under investigation include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
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