**3. Molecular characteristics of GBM**

The current molecular characterization of GBM has allowed different classifications of the tumor subtypes and revealed intracellular pathways that might contribute to the development of new and effective therapeutic targets. The new molecular classification can distinguish individual somatic mutations within the same tumor grade, since tumors are highly variable from patient to patient [6,7]. Thus, using molecular markers facilitate study of heterogeneity of glioma, and subsequently its diagnosis and treatment.

**1. Introduction**

68 Neurooncology - Newer Developments

**2. Epidemiology**

Glioblastoma multiforme (GBM) tumor occurs either as a primary tumor when it is formed de novo or a secondary tumor when the tumor progresses from grade II or III to grade IV. GBM is a diffuse and infiltrative tumor with a high mitotic activity, nuclear atypia, pleomor‐ phism, and necrosis. GBM is the most frequently occurring brain tumor (12–15%) and represents 50–60% of all astrocytomas. There are two variants of glioblastoma: Glioblastoma of giant cells and gliosarcoma. GBM affects the cerebral hemispheres, mostly the white substance of the cerebral hemispheres. GBM primary has a bad prognostic due to its molecu‐ lar heterogeneity. On the basis of its transcriptional subtype, GBM primary is also classified as neural, classical, and mesenchymal as well as proneural for GBM secondary. In GBM primary occurs the amplification of epidermal growth factor (EGF), and the *PTEN* gene is mutated in 45% of GBM primary cases, whereas in GBM secondary, the EGF amplification does not occur. The chromosome alteration in GBM involves a loss of the chromosome 10. The treatment for this kind of tumor after a safe surgical process also involves radiotherapy (RT) and the pharmacological treatment using the alkylating agent Temozolamide (TMZ), and different combinations of this agent with antitumor drugs such as the Bevacizumab. In spite of these treatments, there is a short survival period for GBM patients (14–18 months), which promotes the development of different clinical trials (II or III) to provide the patient a treatment with a better outcome. These new approaches are based on the molecular aspects of GBM to make the treatments more individualized.. This chapter describes the main GBM endocrine and molecular characteristics now known and makes a proposal on future treatments for GBM

The incidence can change by age; in adults, for example, gliomas are the most frequent primary central nervous system tumors recurring in 70% of the patients. The average age of patients with GBM primary is 62 years, while for secondary GBM patients, it is approximately 45 years. The ethnicity and geographical localization are also of great importance in their epidemiology [1]. These tumors represent about 31% of newly diagnosed tumors in the United States and 81% of malignant tumors of the brain. The incidence of brain cancer in Europe is of 5.5/100,000 individuals, and the minor incidence is in sub‐Saharan Africa with 0.8/100,000 individuals [2]. High‐grade gliomas, anaplastic astrocytoma (AA) and GBM, have an incidence of 6.03/100,000 [3,4]. It has been shown that the incidence of GBM with respect to gender and ethnicity was different. The white people had the highest incidence of 2.5/100,000, Latin white people

The current molecular characterization of GBM has allowed different classifications of the tumor subtypes and revealed intracellular pathways that might contribute to the development

patients on the basis of these molecular characteristics.

1.8/100,000, and black people 1.5/100,000 [5].

**3. Molecular characteristics of GBM**

Intensive molecular analyses have revealed a variety of deregulated genetic pathways involved in the DNA damage and repair, apoptosis, cell migration, angiogenesis, and in the cell cycle. Molecular analyses show that they arise from different genomic alterations, which may influence the response to therapy. The Cancer Genome Atlas (TCGA) Research Network (2008) has established a comprehensive catalog of genomic abnormalities driving tumor genesis, thus subclassifying glioblastoma into at least four molecular subtypes, featuring distinct genetic, epigenetic, and transcriptional alterations [6,8]. Tumor variants are classified based on somatic mutations as: isocitrate dehydrogenase (IDH) and Tumor Protein (TP53). Glioblastoma is also classified based on it´s transcriptional signature as: classical, mesenchymal, neural or proneural. Classification is also given by variations in the number of gene copies, by mutations in Epidermal Growth Factor Receptor (EGFR) or by DNA hypermethylation of promotor-associated CpG islands [9].

The majority of glioblastoma cases are primary brain tumors that grow rapidly without major clinical or histological evidence of a less malignant precursor lesion. These tumors mainly affect the elderly and are genetically characterized by loss of heterozygosity (LOH) on 10q, EGFR amplification, p16INK4a deletion, and fosfatidilinositol‐3,4,5‐trisfosfato 3‐ fosfatasa (*PTEN*) mutations [10,11]. Secondary glioblastoma tumors develop through progression from low‐grade diffuse astrocytoma or AA and are pronounced in younger patients [12]. The disruption of tumor‐suppressor gene *TP53* is implicated in the progression of many types of human malignancies; adult glioblastoma patients with *TP53* mutation may have a more severe consequence than those without *TP53* mutations [10]. It has also been shown that *TP53* mutations, but not *p53* expression, correlate with a more aggressive form of the disease. Studies have also reported that glioblastoma with *TP53* mutations are more frequent in women than in men, and may occur in younger patients [13]. In addition, some studies suggest that *TP53* mutations may occur in patients of any age group. In contrast, EGFR amplification preferentially occurs in older patients. Thus, multiple genes are involved in the initiation of the disease, and variability occurs in different age and sex groups in the progression of GBM. It is of interest that after careful analysis of age and disease progression, no significant difference in survival was observed in patients with primary and secondary glioblastoma. During the progression of glioblastoma, additional mutations and genetic alterations accumulate, which may alter disease severity and patient survival.

GBM primary and secondary can also differ significantly, depending on their pattern of promoter methylation and in the expression of profiles at the RNA and protein levels. LOH on 10q is shown to be most frequent in both primary and secondary glioblastomas [14]. *TP53* mutations are detected early in the pathway, and frequent genetic alterations can lead to secondary glioblastoma. In 77 Japanese patients with GBM primary, 22% had *TP53* mutations, 21% *PTEN* mutations, 32% *EGFR* amplification, 42% *p16 INK4a* homozygous deletion, and 69% LOH on chromosome 10q in those patients [15]. The frequencies of these

genetic alterations at the population level were similar to those reported in Europe. This study noted a positive association between *EGFR* amplification and *p16 INK4a* deletion.
