Genetic Diversity of Glioblastoma Multiforme: Impact on Future Therapies

Glioblastoma multiforme (GBM; WHO grade IV) is the most malignant type of glioma and in addition the most abundant malignant cancer of the adult human brain. Despite progress in diagnosis, surgery and chemotherapy, the median survival time of patients suffering from GBM is approximately 15 months (Stupp et al., 2005). The five years survival time is less than 5% (CBTRUS, 2010). Because glioblastoma cells show a highly infiltrating growth into the brain tissue, a total resection is not possible. In addition, glioblastoma cells are remarkably resistant to chemotherapy and ionizing radiation. In addition, the association of a portion of these cells with hypoxic and necrotic areas within the tumor increases their resistance. Gliobastoma multiforme tumors can be classified: 1. by histopathology (WHO) in conventional glioblastomas (93%), giant cell glioblastoma (5%) and gliosarcoma (2%); 2. by pathogenesis in primary GBM (90%) and secondary GBM (10%); 3. by gene expression analysis in (I) classical, (II) mesenchymal, (III) proneural or (IV) neural type of GBM; 4. by genomic analysis in subgroups harboring specific mutations and/or altered gene dosage/chromosome number. Conventional glioblastomas constitute approximately 93% of all glioblastomas and can be divided into primary or secondary tumors: primary glioblastomas represent approximately 90% and develop de novo, whereas the incidence of secondary glioblastomas that arise from astroyctomas WHO grade II and III is in the range of 5 to 10%. Primary and secondary glioblastomas differ in their genetic defects: for example 39% of primary glioblastomas harbor an amplification of the EGF receptor (EGFR) locus, whereas in secondary glioblastomas no amplification was detected. Mutations within the p53 gene are more abundant in secondary glioblastomas. Unconventional glioblastomas include giant cell glioblastomas, gliosarcomas and other rare types (for details see section 4).