The current research in oncology is focused on genetics and molecular oncology in order to obtain better understanding of the etiology of tumor disease. Detailed knowledge of oncogenesis mechanisms could lead to invention of effective therapeutic tools against cancer. Under healthy conditions, cell cycle is regulated by oncogenes and tumor suppressor genes, which should be in strict balance. Genesis of tumor is a consequence of the accumulation of genetic alterations, which help the cell to escape normal cellular regulatory mechanisms and destruction by immune system. Glioblastoma (GBM) is a highly malignant primary brain tumor occurring mostly in population of adults. Patients suffering from GBM have very poor prognosis. Despite development in radiology methods promising earlier diagnosis and development of clinical and radiation oncology with newer treatment regimes, the effect of therapy remains limited and prognosis of patients has not improved as expected. Target of GBM research are genes involved in response to oxidative stress and DNA damage, genes regulating cell cycle, genes determining immune response, growth factors, and others. Genetic alterations are studied in connection to their possible relationship to susceptibility of brain tissue for tumor formation, to sensitivity of brain tissue for various environmental etiology factors, to effect of anticancer treatment or resistance of tumor tissue to therapy, to overall survival, and progression-free interval.
- genetic pathways
Glioblastoma (GBM) is a brain tumor of neuroectodermal origin. It is a second most common primary brain neoplasm and the most common from malignant brain tumors. This tumor arises from neural stem cells (NSCs), progenitor cells, dedifferentiated mature neural cells or neuroepithelial stem cells that transform into cancer stem cells (CSCs) or glioblastoma stem (GSC) or stem-like cells . Stem cells have a high potential of self-renewal and differentiation. GBM is a tumor with highest degree of anaplasia within gliomas. It is classified as grade IV according to the WHO classification of brain tumors from 2007. This lesion has a rapid growth, is unbounded, infiltrates surrounding brain tissue, but rarely metastasizes. When metastases occur, it is usually within the central nervous system. Typical histopathological features of this tumor are cells of recognizably astrocyte origin, but displaying cellular pleomorphism with multinucleation, frequent mitoses, and areas of necrosis surrounded by palisading nuclei (increased tumor cell density) and endothelial proliferation as a manifestation of cellular hyperplasia with numerous clusters of blood vessels forming so-called glomeruloid formations. GBM cells spread along tracts in white matter infiltrate cerebrospinal fluid and vessels between meningeal layers. Invasion of GBM cells begins with the degradation of surrounding matrix proteins by proteases and proteinases. Movement of tumor cells through surrounding brain tissue requires receptor turnover, formation and degradation of focal adhesion molecules and rearrangement of cytoskeleton components. These changes are consequences of genetic alterations, such as overexpression, amplification, deletion or mutation in focal adhesion kinase and phosphatidylinositol 3-kinase (PI3K) pathways  and mainly caused by activation of growth factors and their receptors (integrins and protein deleted in colorectal cancer (DCC), hyaluron receptors CD44, RHAMM, BEHAB, ontogenetic protein SPARC, receptors for platelet-derived growth factor (PDGF), transforming growth factor (TGF)-α, epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF)). Some components of extracellular matrix such as laminin or fibronectin are overexpressed in GBM and their silencing reduces invasiveness of GBM cells . Besides microscopic characteristics, GBM is connected with a huge amount of genetic alterations causing higher proliferation, migration, and invasiveness of tumor cells. The intrinsic ability of GBM cells to invade normal brain tissue impedes complete surgical resection and predictably results in early local recurrence and mortality. Thoroughgoing explanation of GBM genetic pathways with their gene alterations is necessary for choosing of more suitable therapy and in predicting patient prognosis. This chapter offers an overview of the most common genetic alterations occurring in GBM.
2. Classification of GBM
According to the WHO classification of brain tumors based on histopathological origin, GBM is a primary brain tumor of neuroepithelial, glial origin. Ranking of GBM in clinical and prognostic significance is within the highest grade IV. GBM could also be classified according to mode of occurrence, as it could be a result of progression from less malignant glial tumor (so-called secondary type) or it could occur de novo (primary type). Another specific type is pediatric GBM. The most common is primary type. Primary, secondary, and pediatric GBMs have their own specific genetic and epigenetic alterations occurring in their gliomagenesis (see Figure 1). As diagnosis of GBM presents with heterogeneity of altered genetic pathways evidenced by The Cancer Genome Atlas Research Network’s study, classification based on gene expression profile distinguishes a classical, mesenchymal, proneural, and neural type of GBM. Classical type typically harbors no TP53 mutations, but very high rate of epidermal growth factor receptor (EGFR) mutations. This type has a slightly better survival. Mesenchymal type displays frequent mutations of neurofibromatosis gene 1 (NF1), TP53, and PTEN genes and aggressive anticancer therapy brings a significant increase in survival of these patients. Third, proneural subtype presents with highest mutation rate of TP53, PDGFRA, and isocitrate dehydrogenase (IDH) and usually affects younger adults. Last, neural type occurs more often in older population and contains several gene mutations at an average rate . These classifications show high heterogeneity of genetic profile, aggressiveness, clinical characteristics, and expected prognosis of GBM patients with a strong need of definite uniform classification of subtypes leading to more specific treatment for each GBM subtype.
3. Most frequent genetic alterations of GBM
As mentioned above, alterations of oncogenes and tumor suppressor genes could deflect cell from normal cell cycle. Accumulation of genetic alterations of these genes initiates oncogenesis. In oncogenes, lesion of one allele is sufficient to cause mutation. Activation of oncogene causes avoidance of apoptosis and cell further proliferates. Amplification and activating mutation are the most common genetic alteration of oncogenes. On the other hand, lesion of both alleles is required to evoke mutation in tumor suppressor genes. These genes and their protein products when activated inhibit cell proliferation. Frequently observed alterations are deletion and inhibitory mutation.
During years of genetic research, there have been established three critical genetic pathways whose alterations lead to the formation of GBM: inactivation of p53 and retinoblastoma (RB) pathways (see Figure 2), activation of the PI3K pathway, and deregulation of growth factor (receptor tyrosine kinase—RTK) signaling (see Figure 3). TP53 signaling pathway is altered in 87% of GBMs, mostly affecting p53, murine double minute-2 (MDM2), MDM4, and cyclin-dependent kinase (CDK)N2A genes. Approximately 78% of GBMs harbor RB signaling disruption with most frequently altered genes: RB1, CDK4, CDK6, CCND2, and cyclin-dependent kinase inhibitor 2 (CDKN2) family. Finally, RTK/RAS/PI3K activation was found in 88% of tumors, affecting usually NF1, PIK3R1, and PIK3CA genes.
GBM is classified as primary or secondary according to altered genes. Primary GBM is a tumor with de novo formation. On the other hand, GBM as a result of malignant transformation of lower-grade glial tumor is called secondary . Also, clinical manifestation and age of diagnosis vary within these two types. Typical for primary GBM is very short anamnesis and age over 50. On the contrary, patients with secondary GBM usually have previous anamnesis of lower grade glioma and younger age depending on the age at the time of diagnosis of preexisting lower grade glioma. Both – primary and secondary GBM – have their own specific gene alterations occurring in their gliomagenesis (see Figure 1). Typical alterations for primary GBM are homozygous deletion or mutation of
On 9p21 are located genes
Gene phosphatase and tensin homology –
Signal transducer and activator of transcription 3 –
Paternally expressed gene 3 –
Vascular endothelial growth factor –
The B-Raf proto-oncogene serine/threonine kinase –
H3 histone, family 3A –
Telomerase reverse transcriptase –
GBM is the most aggressive and devastating primary brain tumor with very grim prognosis. The patient’s survival rarely exceeds a year and a half with all accessible therapy used. Only 3% of GBM patients have survival over 5 years. This fact makes this tumor a very severe diagnosis directly affecting life expectancy of the patient and quality of his/her life. Explanation of its genesis could bring us closer to invention of effective treatment and genetic profile of concrete GBM tissue would help to design the individualized therapy management for each patient. Understanding the genetic and epigenetic characterization could help to distinguish various GBM subgroups, indistinguishable by histological appearance, but classified according to molecular and genetic alterations. This could lead to establishment of GBM classification with clinical impact, subgroup-specific treatment, and better design of future trials. The aim was to achieve prolonged progression-free interval and overall survival with maintaining satisfactory quality of life. It is very important if concrete genetic alteration is connected to tumor formation or if it is prognostic factor. Other factors influencing prognosis are histological type and tumor grade, age of patient, Karnofsky performance score at the time of diagnosis, extend of surgical resection, tumor localization, and appropriate therapeutic management. Tumor localization and extend of its surgical resection influence progression-free interval as well as overall survival. Detailed and complete explanation and discovery of altered genes and whole genetic pathways of GBM is the basis for new distinctive GBM classification. Such a new tumor division could bring us closer to routine genetic examination of frequently altered genetic pathways from tumor sample and aiming of therapy directly against specific genetic and epigenetic targets. Such individualized therapy could decrease the number of adverse effects, but first of all, hopefully, would finally ameliorate survival and life quality of patients, suffering from this severe disease.
This work was supported by projects: Competence Center for Research and Development in the diagnosis and therapy of oncological diseases, ITMS 26220220153 and The application of PACS (Picture Archiving and Communication System) in the reasearch and development, ITMS 26210120004.
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