Vol 9, Issue 2, 2021 ISSN - 2321-4406 THE ASSOCIATION BETWEEN TRAUMATIC BRAIN INJURY AND GLIOMAGENESIS AND ITS SPECIAL ROLE IN GLIOBLASTOMA MULTIFORME PATHOGENESIS: A REVIEW NIKOLAOS ANDREAS CHRYSANTHAKOPOULOS 1 , PANAGIOTIS ANDREAS CHRYSANTHAKOPOULOS 2 1 Department of Pathological Anatomy, Medical School, University of Athens, Athens, Greece. 2 Department of Neurosurgery, Military Hospital of Athens, Athens, Greece. Email: nikolaos_c@hotmail.com/nchrysant@med.uoa.gr Received: 05 December 2020, Revised and Accepted: 25 January 2021 ABSTRACT Gliomas are the most common primary and aggressive intracranial tumors, represent 80% of malignant brain tumors, and despite the fact that are relatively rare tumors are responsible for significant mortality and morbidity. Glioblastoma multiforme (GBM) or diffuse astrocytoma, WHO grade IV, is the most common and aggressive primary central nervous system malignancy, represents 45% of all gliomas, shows an average incidence of 3.19/100,000 individuals, its median age of diagnosis is 64 years, and the median survival is 15 months as the 5-year relative survival is 5%. Previous studies have investigated the possible role of genetic and environmental factors in GBM pathogenesis; however, the majority of GBM cases were sporadic and certain risk factors have not been detected. GBM is divided into primary and secondary subtypes which develop through different genetic pathways, affect patients at different ages, and have differences in clinical outcomes, as show a great morphological and genetic heterogeneity. The role of traumatic brain injury (TBI) in GBM formation has been investigated in many previous reports which have hypothesized that TBI may predispose to gliomagenesis; however, the outcomes were highly controversial. Some of those researches have proposed a supposed pathogenesis model that involves a post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis. Other similar studies have involved transcription factors associated with TBI such as p53, hypoxia-inducible factor-1a (HIF-1a), and c-Myc. On the other hand, the possibility of a pre- existing tumor rather than a trauma-induced tumor is very possible in such cases. Keywords: Gliomas, Glioblastoma, Signaling Pathways, Inflammation. INTRODUCTION Gliomas are primary brain tumors, and classified according to their supposed origin cell, as astrocytic tumors (astrocytoma, anaplastic astrocytoma, and glioblastoma), oligodendrogliomas, ependymomas, and mixed gliomas [1]. They are the most common primary and aggressive central nervous system tumors which account for almost 80% of all malignant primary brain tumors [1,2]. In general, gliomas are more common in males than females, with the exception of pilocytic astrocytoma, which occurs at similar rates in males and females [3]. Anaplastic astrocytoma and glioblastoma multiforme (GBM) increase in incidence with age, peaking in the 75–84 age group. Oligodendrogliomas and oligoastrocytomas are the most common in the 35–44 age group [4]. GBM or diffuse astrocytoma, WHO grade IV [5], is the most malignant and frequent type of primary astrocytomas, as accounts for more than 60% of all brain tumors in adults [6], is characterized by extremely poor prognosis, despite developments in molecular Biology and genetics and new anti-neoplasmatic treatments and shows a great morphological and genetic heterogeneity, whereas its median survival is about 14–15 months after its diagnosis [7,8]. GBM’s global incidence is <10/100,000 individuals [8], accounts for 50% of all gliomas age but the peak incidence concerns individuals between ages 55 and 60 [9], is the 3 rd principal cause of death from cancer in individuals 15 and 34 years of age [10], whereas the GBM incidence ratio is higher in males than in females [8,9]. Brain neoplasms etiology has not yet been clarified as no underlying carcinogenetic factors have been identified. Until now the only confirmed risk factor is exposure to high dose ionizing radiation [11,12]; however, the overall risk of developing GBM following radiotherapy is 2.5% [13]. Extensive retrospective cohort data showed a higher risk of glioma in pediatric populations after exposure to therapeutic intracranial radiation. Data in adults are more limited but showed increased risk in certain groups exposed to radiation. No evidence was found between risk of developing GBM and routine exposure to diagnostic radiation in both children and adults [14]. Furthermore, patients who received treatment for acute lymphoid leukemia (ALL) were more prone to develop GBM, as a result of complications arising from the leukemia or the chemotherapeutic agents used to treat ALL [13]. No conclusive association has been found between GBM and environmental factors such as smoking, dietary risk factors, cell phones or electromagnetic field, human cytomegalovirus infection, occupational risk factors, and pesticide exposure [1,12,15-17]. Few studies have shown the possible role of ovarian steroid hormones in development of GBM [18]. It has also been proposed that infections and allergic diseases may have a protective effect for GBM that may be due to the activation of immune surveillance mechanism [5,11]. Gliomas also tend to run in families but the susceptibility gene is still unidentified [11]. Genetic predisposition has been observed only in 5–10% of cases [15]. Family history has been shown to be associated with an increased risk of GBM. Recent genome-wide association studies have indicated single nucleotide polymorphisms (SNPs) that can increase the predisposition to glioma development [19-24]. Such a significant SNP is located on chromosome 8q24.21, within the locus of a long non-coding RNA named CCDC26, which increases glioma risk approximately 5 times [19-21]. Infrequent genetic diseases such as neurofibromatosis type 1 and type 2, and tuberous sclerosis, were found to be associated with increased GBM incidence [11,12,16]. Environmental risk factors in GBM development remain poorly defined, as already has been mentioned, with the exception of exposure to ionizing radiation. Another possible risk factor for gliomagenesis is traumatic brain injury (TBI) [25-27]. Review Article © 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijms.2021v9i2.40457. 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