Although there is only indirect evidence for an association between viruses and certain primary tumors of the nervous system, epidemiologic and experimental data—drawn from studies of the human papillomavirus and the hepatitis B, Epstein-Barr, and human T-lymphotropic viruses—indicate that they may be involved or act as risk factors in certain human cancers. The genes of Epstein-Barr virus (EBV), for example, are incorporated into the DNA of many cerebral lymphomas. In transgenic mice, certain viruses are capable of inducing olfactory neuroblastomas and neurofibromas. Each of these viruses possesses a small number of genes that are incorporated in a cellular component of the nervous system (usually a dividing cell such as an astrocyte, oligodendrocyte, ependymocyte, endothelial cell, or lymphocyte). The virus is believed to act to force the cell from its normal activity into an unrestrained replicative cycle. Because of this capacity to transform the cellular genome, the virus product is called an oncogene; such oncogenes are capable of immortalizing, so to speak, the stimulated cell to form a tumor. Oncogenes are also found in normal cells and may contain mutations or are capable of being activated by cellular and environmental (epigenetic) events as noted later.
Molecular and genetic features of brain tumors The above concepts have been expanded greatly by the identification of certain genetic aberrations that arise in tumor cells of the nervous system. What has emerged from these studies is the view that the biogenesis and progression of brain tumors are a consequence of defects in the control of the cell cycle. Some molecular defects predispose to tumor genesis; others underlie subsequent progression and accelerated malignant transformation and yet others may confer sensitivity or resistance to chemotherapeutic agents. This model presupposes the acquisition of multiple genetic defects over time since, with the exception of special inherited conditions such as neurofibromatosis, ataxia telangectasia, and a few others, these are not germ line mutations but are acquired as somatic events in the course of tumor evolution.
Typically, inherited mutations affect only one of two copies of a tumor suppressor gene that, by itself, does not cause cancer. However, if the second copy of the gene acquires a mutation (e.g., from a chemical toxin or irradiation) the tumor suppression function of the gene is lost and neoplastic transformation of the cell becomes likely. These ideas are consistent with the observation that many of the gene defects that predispose to cancer are dominantly inherited. More recently, single nucleotide polymorphisms have been identified that in combination predispose to certain childhood tumors such as neuroblastoma, or to the more aggressive forms of various tumors.
In the glioma tumor line, somatic (acquired) mutations in IDH1, EGFR, ATRX, and TERT have proved to be predictive of tumor behavior and prognosis. Another comparable example occurs in oligodendrogliomas that have combined deletions (codeletion) in chromosomes 1p and 19q and as a result, respond well to chemotherapy, a property that increases survival (Reifenberger and Louis; Louis et al, 2002). The childhood tumors of neuroectodermal origin would seem to be particularly attractive as models to explore genetic alterations and indeed, various changes such as the amplification of the MYCN oncogene has been associated with an aggressive clinical course and poor outcome in neuroblastoma and medulloblastoma.
Details of the genetics pertaining to gliomas in particular are given in a later section.
On the basis of this molecular information, views of the pathogenesis of neoplasia are being cast along new lines. Some of the specifics of these new data are presented in the following discussions of particular tumor types. A more extensive overview can be found in the article by Osborne and colleagues, and the text by Kaye and Laws.
Pathophysiology of Brain Tumors