Glioma biology and molecular markers

The tumors classified as gliomas include a wide variety of histologies including the more common (astrocytoma, glioblastoma), as well as the less common histologies (oligodendroglioma, mixed oligoastrocytoma, pilocytic astrocytoma). Recent efforts at comprehensive genetic characterization of various primary brain tumor types have identified a number of common alterations and pathways common to multiple tumor types. Common pathways in glioma biology include growth factor receptor tyrosine kinases and their downstream signaling via the MAP kinase cascade or PI3K signaling, loss of apoptosis through p53, cell cycle regulation, angiogenesis via VEGF signaling, and invasion. However, in addition to these common general pathway alterations, a number of specific alterations have been identified in particular tumor types, and a number of these have direct therapeutic implications. These include mutations or fusions in the BRAF gene seen in pilocytic astrocytomas (and gangliogliomas). In oligodendrogliomas, mutations in IDH1 and codeletion of chromosomes 1p and 19q are associated with improved survival with upfront use of combined chemotherapy and radiation, and these tumors also have unique mutations of CIC and FUBP1 genes. Low grade gliomas are increasingly seen to be divided into two groups based on IDH mutation status, with astrocytomas developing through IDH mutation followed by p53 mutation, while poor prognosis low grade gliomas and primary glioblastomas (GBMs) are characterized by EGFR amplification, loss of PTEN, and loss of cyclin-dependent kinase inhibitors. GBMs can be further characterized based on gene expression and gene methylation patterns into three or four distinct subgroups. Prognostic markers in diffuse gliomas include IDH mutation, 1p/19q codeletion, and MGMT methylation, and MGMT is also a predictive marker in elderly patients with glioblastoma treated with temozolomide monotherapy.