**7. Pediatric brain tumor**

The pediatric brain tumor is the second most childhood malignant brain tumor and the most common solid tumor in children. The genetic syndromes that cause brain tumors are due to NF-1, tuberous sclerosis, Li-Fraumeni syndrome, and other less common inherited conditions, such as Gorlin syndrome or Turcot syndrome [76].

1.low-grade glioma

Low-grade gliomas (LGGs) is the most common pediatric central nervous system (CNS) tumor and it comprises for 30–40% of all CNS tumor. LGGs are infiltrative and incurable primary brain tumors with a typical slow evolution. Treatment of this low-grade glioma includes chemotherapy, radiation therapy, and targeted therapy [77].

#### 2.High-grade glioma

High grade comprises up to 12% of pediatric CNS tumors and it includes anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV)*.* The symptoms depend on tumor location. The treatment method includes chemotherapy regimens that have been studied in the patients with highgrade gliomas, including temozolomide, lomustine, and thalidomide but have unfortunately not resulted in significant improvement in survival rates [78].

3.Medulloblastoma

Medulloblastoma is the most common CNS embryonal tumor. It represents about 10% of all pediatric brain tumors [79]. Medulloblastoma is the most common malignant brain tumor in children accounting for approximately 25% of pediatric brain tumors, with many reports indicating an increase in medulloblastoma in recent years [80].

4.Ependymoma

Ependymomas are tumors of the central nervous system that derive from the ependymal cells that line the ventricles of the brain and the central canal of the spinal cord [81]. Ependymoma can occur throughout the neuroaxis-supratentorial, posterior fossa, and spinal cord; however, 90% of pediatric ependymomas occur intracranially with 2/3 in the posterior fossa and 1/3 supratentorially [82].

#### **8. Molecular genetics of brain tumor**

The molecular genetics of brain tumors is due to the mutation in enzymatic activity. The mutation rate that commonly occurs in various gene to cause brain tumor are:


IDH catalyzes the oxidative decarboxylation of isocitrate to generate (-KG) and CO2, however, mutant IDH1/2 preferentially binds -KG rather than isocitrate outside of the citric acid cycle, resulting in the formation and accumulation of the oncometabolite 2-hydroxyglutarate (2HG) [84].

HIF1 (Hypoxia Inducible Factor) levels and alterations in the HIF1 downstream pathway are modulated by -KG–dependent prolyl hydroxylases, resulting in an increase in reactive oxygen species levels and potentially contributing to the risk of cancer [85].

B. TP53 mutation

TP53 is a tumor suppressor gene that encodes the nuclear protein p53 and is found on the 17p13.1 chromosome [86]. Several human malignancies, including Li-Fraumeni syndrome and numerous hereditary gliomas, are linked to mutated TP53 genes and over-expressed aberrant p53 protein, which has a longer half-life than wild type p53 [87].

C. ATRX is an X-linked gene of α- Thalassemia and mental retardation syndrome

ATRX is a 280-kDa nuclear protein that has been implicated in a variety of biological activities including DNA recombination, repair, and transcription control. It is found on chromosome 21.1 and encodes a 280-kDa nuclear protein [88]. When ATRX and DAXX connect, the resulting complex acts as a histone chaperone, allowing histone variation H3.3 to be deposited into heterochromatic repeats such as pericentric, telomeric, and ribosomal DNA repeat regions [89].

D.EGFR amplification and EGFRvIII truncation mutation

EGFR, also known as Erb1 or HER1, is an ErbB family receptor tyrosine kinase that is found on chromosome 7q12. EGFR over-expression is linked to EGFR amplification. The EGFRvIII mutation is a frame deletion of 801 bytes from exons 2 to 7 of the EGFR gene, which is linked to EGFR amplification, antibody response, and poor prognosis [90, 91].

E. BRAF mutation

Pilocytic astrocytoma is defined by BRAF V600E mutations and BRAF fusions with KIAA1549 or FAM131B. A tandem duplication at 7q34 was verified, and a novel fusion gene was discovered in pilocytic astrocytoma, which was previously uncharacterized by a fusion between the KIAA1549 and BRAF genes [92].
