Glioma cancer genes

Glioma is a set of tumors that occur in glial cells; glial cells surround and support nerve cells (NCI 2013). The most common subtype of glioma is glioblastoma (GBM), and it is also one of the most difficult cancers to treat. Approximately 22,400 gliomas are diagnosed in the U.S. each year; of those, approximately 12,075 are GBMs (CBTRUS 2012). The 2-year survival rate for GBM is about 27% with standard therapy (Stupp et al. 2009).

In 2007, the World Health Organization defined the current diagnostic categories for gliomas (Louis et al. 2007). Glioma subtypes are defined by presumed cell of origin as well as by invasiveness. Grade I tumors are generally circumscribed and potentially curable by resection. Glioma grades II–IV are diffusely infiltrating and grade IV is highly invasive (Dang, Jin, and Su 2010). The degree of tumor aggressiveness, as defined by proliferation and rapidity of spread, increases with increasing tumor grade and grade I and II are classified as low grade tumors whereas grade III and IV are classified as high grade tumors. The diffuse gliomas include astrocytoma, oligodendroglioma, and oligoastrocytoma, named according to the cell type they resemble under the microscope (Louis et al. 2007). Astrocytomas are the most common subtype of glioma and morphologically resemble astrocytes; astrocytomas most often present as aggressive WHO grade IV glioblastomas (GBM). So called “primary” GBMs develop de novo with no prior history of brain cancer, while “secondary” GBMs progress from lower-grade II and III astrocytomas (Kleihues and Ohgaki 1999). Oligodendrogliomas morphologically resemble oligodendroglial cells and, like astrocytomas, infiltrate the brain. Oligodendrogliomas are not as aggressive as astrocytic tumors with a similar grade and thus have a longer survival. Ependymomas are yet another subclass of glioma; they originate from ependymal cells. Ependymomas do not show the infiltrative behavior seen in astrocytomas and oligodendrogliomas, and therefore surgical resection can be curative. However in the absence of complete surgical resection ependymomas can recur and metastasize within the central nervous system.

The standard treatment for newly diagnosed glioblastoma (grade IV) is biopsy or surgical resection, depending on location of the tumor, followed by treatment with radiotherapy and temozolomide (Dubrow et al. 2013). Treatment for grade I-III gliomas may include biopsy or surgery, and may include chemotherapy or radiotherapy, less frequently (NCI 2013; Omay, Piepmeier, and Knisely 2012).

The Cancer Genome Atlas (TCGA) and other groups have recently classified glioblastoma into gene expression-based subtypes (Phillips et al. 2006; TCGA 2008; Verhaak et al. 2010). These include classical, mesenchymal, neural, and proneural subtypes. Verhaak and colleagues furthered our understanding of the GBM subtypes by correlating genomic data, including DNA mutation and gene copy number changes, with gene expression data (Verhaak et al. 2010, reviewed in Goodenberger and Jenkins 2012). They found classical tumors to be characterized by chromosome 7 gain with amplification of the epidermal growth factor receptor (EGFR), EGFR mutation, and chromosome 10 loss. Mesenchymal tumors are characterized by low levels of NF1 expression together with high expression of genes in the tumor necrosis factor (TNF) family and NF-κB pathway. The neural subtype of glioblastoma expresses proteins associated with neuronal differentiation, and shows features intermediate between proneural and mesenchymal tumors. The majority of “secondary” GBMs (those that progress from lower-grade II and III astrocytomas) are of the proneural subtype. Proneural tumors are characterized by mutations in isocitrate dehydrogenase genes IDH1 and IDH2, and the tumor suppressor p53. Moreover, IDH mutated GBMs have a unique DNA methylation status termed CIMP (CpG island methylator phenotype) and CIMP positive tumors are also proneural but not all proneural GBMs have the CIMP eptitype. Pronerual GBMs with the CIMP epitype have the best prognosis of all subtypes of glioblastomas including proneural GBMs without CIMP.

IDH1/2 mutations have been shown to be early events in gliomagenesis. Two major genetic subtypes of IDH-mutated gliomas have been identified. One subtype defined by TP53 and alpha-thalassemia/mental retardation syndrome x-linked (ATRX) mutations that correlates with an astrocytoma histology (Wakimoto et al. 2014); a second type is characterized by concurrent mutations in homolog of Drosophila capicua (CIC), far upstream element binding protein (FUBP1), telomerase reverse transcriptase (TERT) promoter, and 1p/19q codeletion and is associated with an oligodendroglioma histology. IDH/CIC-mutated tumors are associated with PIK3CA/KRAS mutations, whereas IDH/TP53 tumors are associated with PDGFRA/MET amplification.

The effects of several targeted agents have been studied in glioma: BRAF, EGFR, MEK, PDGFR, VEGF, and other inhibitors have all been tested or are being tested in clinical trials (ClinicalTrials.gov; Patil et al. 2013). A humanized anti-VEGF antibody bevacizumab, an antiangiogenesis agent, is approved by the U.S. FDA for use in recurrent GBM (Patil et al. 2013).