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Major advances in the field of molecular biology have led to identification of a number of genetic abnormalities that predispose to the development of GBM. Although only a tiny fraction of primary central nervous system neoplasms occur in the setting of an inheritable disorder or syndrome, substantial evidence of genetic factors in their development has existed for some time. Two well-known examples are Turcot syndrome (colonic adenomatous polyposis, medulloblastoma, and malignant glioma) (17,18) and neurofibromatosis type 1 (increased prevalence of many tumors, including all grades of glioma and breast cancer) (19). Another less well-known example is the Li-Fraumeni syndrome of familial neoplasms in various organs, including breast, bone, blood, soft tissues, and brain (20).
The term oncogene is used to describe genes that encode for proteins that directly promote neoplastic transformation and stimulate tumor growth. These abnormal genes may occur from a sporadic mutation or may be inherited as a germline mutation. Tumor-suppressor genes (also referred to as "wild type" genes), on the other hand, are normal genes present in most people. They encode for proteins that control the growth of normal tissues and prevent neoplastic growth and transformation. Either the absence of a tumor-suppressor gene or the mutation into an oncogene can lead to increased prevalence of neoplasms in various body tissues. Both oncogenes and malfunctioning tumor-suppressor genes have been identified in patients with GBMs.
Perhaps the best known tumor-suppressor gene is p53, which is located on the short arm of chromosome 17. An abnormal p53 gene has been implicated in a wide variety of tumors throughout the body, such as in the Li-Fraumeni syndrome, and studies have shown that at least 40% of GBMs have this mutation (21,22). Because an abnormal p53 gene seems to be more common in higher-grade astrocytomas, it is thought to contribute to the natural progression of low-grade to higher-grade astrocytomas (23). There is also evidence that it plays a role in the initial neoplastic transformation of a normal glial cell into an astrocytoma. In vitro studies have demonstrated partial growth stoppage in GBM after insertion of a normal p53 gene into GBM cells (24) and after direct administration of normal p53 protein to GBM cell colonies.
Many other tumor-suppressor gene mutations and oncogenes have been identified and are being actively studied. Because of the wide genotypic and phenotypic variation found in GBM, most researchers support a multistep theory of tumorigenesis, in which many areas of genetic abnormality coexist simultaneously. These genetic lesions may be caused by inherited or acquired mutations and progressively disrupt the natural cellular balance between the positive and negative regulators of cellular growth and differentiation (25). It has been clearly documented that there is a direct relationship between the number and degree of detectable genetic abnormalities and the type and grade of the glioma. Simple astrocytomas (World Health Organization [WHO] grade II) may show no demonstrable karyotypic abnormalities, whereas anaplastic astrocytomas (WHO grade III) display variable genetic damage. GBMs (WHO grade IV) that have been karyotyped invariably show multiple loci of genetic abnormality and chromosomal derangement. One specific pathway for the development of GBM involves mutation of p53 at the astrocytoma stage; loss of tumor-suppressor genes on chromosomes 9, 13, or 19 to produce an anaplastic astrocytoma; and subsequent loss of tumor-suppressor genes on chromosome 10 in the transformation to a GBM (26). Although not as well studied as p53 mutation, allelic loss from chromosome 10 appears to be the most common genetic lesion in GBM and is found in up to 80% of specimens (27). Unlike p53 mutation, chromosome 10 damage does not appear to be common in other tumors in the body nor in lower grades of glioma, a finding that suggests chromosome 10 damage may be specific for GBM.
Current research suggests that primary GBM, which arises de novo, may have a genetic basis different from that of secondary GBM, which arises within a preexisting lower grade glioma (16). The overexpression of epidermal growth factor receptor appears to occur in the absence of p53 mutations in 90% of GBMs that are clinically considered likely to be primary. The possibility that these less common primary GBMs may arise through a mutation of the epidermal growth factor receptor represents an intriguing hypothesis but warrants further investigation.
How do these areas of genetic alteration occur? Some are inherited, such as in the Li-Fraumeni syndrome, in which abnormality in the p53 gene is inherited through a germline mutation. Others may be related to environmental mutagens such as radiation and certain chemical substances, such as vinyl chlorides. There is evidence suggesting that low-grade astrocytomas in children that were irradiated have a slightly higher prevalence of undergoing malignant transformation than nonirradiated tumors (28,29). The increased prevalence of multifocal gliomas in patients who have previously been treated for acute lymphocytic leukemia suggests that chemotherapeutic agents, in particular intrathecal methotrexate, may have a synergistic effect with radiation in the generation of these tumors (30). Other potential environmental factors that have been suggested but not substantiated include proximity to electromagnetic fields generated by high-power lines.
The overwhelming majority of patients with GBMs have no history of irradiation or specific toxic exposure. Given the increased prevalence of GBM with age, it seems plausible that genetic injuries occur all the time for many reasons and that normal repair mechanisms may not be able to keep up with the ongoing deterioration of genes. Thus, genetic insults gradually accumulate, which in turn causes the progressive neoplastic transformation of normal glial cell lines into low-grade glioma and subsequently GBM.
Etiology and Genetics