**4. Conclusion**

The B-Raf proto-oncogene serine/threonine kinase – **BRAF** gene, located on 7q34, is a member of Raf kinase family and serves as a strong activator of the extracellular signal-regulated kinase/ mitogen-activated protein kinase 1 and 2 (Erk 1/2) signal transduction cascade which modu‐ lates cell growth, proliferation, migration, differentiation, and apoptosis. Mutations of BRAF gene usually occur at codon 600, which is a site of activation loop of the kinase domain. Consequence of this BRAF V600E mutation is a protein with increased kinase activity. This mutation is usually present in lower-grade gliomas, but was found in 54% of epithelioid GBM [90], in 7% of giant cell GBM [91]. Within classical GBM types, BRAF mutation was present in 8% of adult and in 12% of pediatric GBM cases. These GBMs were all classified as primary. In adults, they create a group of tumors that are present in younger age (mean age of 39 years), none of these tumors harbored IDH mutation and seem to have slightly longer survival [92]. GBMs with BRAF V600E mutation may represent a small, but more favorable subgroup. In such patients, BRAF/MEK inhibitor treatment may be beneficial in combination with other

H3 histone, family 3A – **H3F3A** gene, located on 1q42.12, encodes replication-independent histone H3.3. Histones are basic nuclear proteins responsible for the nucleosome structure of the chromosomal fiber. ATRX and DAXX genes are encoding subunits of a chromatin remod‐ eling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres [94]. The histone H3.3 mutations result in amino acid substitution at K27 or G34 – two critical positions within the histone tail involved in key regulatory posttranslational modifications. H3F3A mutations are often seen in tumors with somatic TP53 mutation, within histological grades are specific for GBM and are highly prevalent in children and young adults, and they are present in one-third of pediatric GBMs [95]. Interestingly, K27-mutated tumors were predominantly seen in midline structures – thalamus, pons (diffuse intrinsic pontine gliomas), and spinal cord and have potentially poor prognosis. G34-mutated GBMs have better overall

Telomerase reverse transcriptase –**TERT** gene is located on 5p15.33. This gene encodes the enzymatic core of telomerase. Telomeres are repeated sequences of DNA at the ends of chromosomes. Under physiological conditions, as the cell divides, telomeres become progres‐ sively shorter. Telomerase counteracts the shortening of telomeres by adding small segments of DNA at the end of chromosome after each cell division. Enhanced telomerase activity facilitates cellular immortality and promotes oncogenesis. Mutations of TERT promoter unmask binding sites for transcription factors, upregulate TERT expression and cellular telomerase activity [97]. TERT mutations are much more common in primary GBM and are inversely correlated with IDH mutations. Primary GBMs with TERT mutation exhibit signif‐ icantly shorter overall survival than TERT-wild type tumors [98]. This unfavorable prognosis was absent after gross total resection and temozolomide therapy, what may indicate that TERT

Tumor suppressor **PARK2** gene (parkin RBR E3 ubiquitin protein ligase) has locus on 6q25.2 q27. The exact function of this gene is still to be explored. It codes an E3 ubiquitin ligase mediating the targeting of substrate proteins for proteasome degradation. Germ line mutations of this gene cause Parkinson's disease, somatic mutations contribute to cancer. PARK2 is one

mutation makes tumor more susceptible to chemotherapy.

therapies [93].

96 Neurooncology - Newer Developments

survival [96].

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 accord‐ ing 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.
