**6. Possible relationships between location and genetic signature in primary brain tumors**

A unique finding is that the location of certain primary brain tumors determines their genetic characteristics. Cranial base meningiomas are less malignant compared to the non-cranial base meningiomas [85]. The frequencies of grade II and III cranial base and non-cranial base meningiomas are 3.5 and 12.1%, respectively. These findings origin from a clinical-patholog‐ ical observation. The biological, molecular, and genetic basis of this fact requires further explanation. A simple answer would be the diverse embryological origins of the dura mater in various locations of human skull [86]. A recently published paper showed (utmost) intriguing data about meningioma biology, which is going to help our understanding of this tumor, of which 85–90% is classified as benign (grade I), but has in certain locations an aggressive course. Meningiomas regarding their genetic origin are divided as NF2 and non-NF2 meningiomas. The non-NF2 meningiomas behave clinically different and are generally always benign, with chromosomal stability, and originate from the medial skull base. In contrastto these findings, meningiomas with mutant NF2 and/or chromosome 22 loss are more likely to be atypical and demonstrate genomic instability and are localized to the cerebral and cerebellar hemispheres. This group concludes their study: "Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics" [87]. There is a mutational profile of a meningioma, which can be predicted based on its anatomi‐ cal location in human calvarium. This finding may provide a unique treatment strategy for midline tumors, which may have a response to medical treatment like hedgehog inhibitors. There are treatment-resistant meningiomas, which are surgically unresectable, recurrent, or invasive. In these patients one can reserve surgery or irradiation, bearing in mind that there is an independent risk factor for progression of these generally benign considered primary brain tumors. This location-based molecular and genetic data provides an updated information about prognosis and treatment response of meningiomas. This update research, which is collected over 300 meningiomas, is a valuable finding, regarding designing personalized management strategies for meningiomas.

Another fact about meningioma is that there is a subgroup of meningiomas, which are histopathologically classified as grade I meningioma, but recurs during follow-up in a short distance unexpectedly as grade II and later as grade III meningiomas. Although the malig‐ nant progression of gliomas is considerably well defined and researched entity, there is lack of scientific data about meningiomas, regarding which one is going to transform malignant‐ ly. Al-Mefty et al. explained this clinical observation with their FISH analysis of primary and recurring meningiomas with malignant progression in their series. They studied 175 recur‐ rent meningiomas and found that 11 tumors showed histopathologically verified progres‐ sion to a higher grade. In this study, the cytogenetic analysis with FISH showed deletions of 22, 1p, and 14q. The interesting finding was that in all but one case, these aberrations have been shown to be also present in the previous specimen despite their lower histopathologi‐ cal grades [88].

The conclusion of this translational paper from 2004 was defined: "Tumors that present with complex genetic alterations, even those with a benign histopathological grade are potential‐ ly aggressive and require closer follow-up." After 12 years this sentence is still valid for meningiomas and other primary brain tumors, which are genetically prone to upgrade. The designated malignant progression of primary brain tumors is an important issue for design‐ ing molecular-genetic-based therapeutic approaches in the near future. The finding that oligodendrogliomas show allelic deletions on 19q and 1p has been defined in 1994 by Reifenberger et al. [89]. Clinical relevance and its implication in changing management strategies followed this genetic finding. The chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas were explained with the over-mentioned genetic background [90]. Its relationship with better prognosis and response to chemotherapy is today an established fact and will be considered in the update "integrated-layered" classification of central nervous system tumors after Haarlem consensus [91]. The location of oligodendro‐ gliomas and its relationship with 1p19q deletion further changed our direction in a phyloge‐ netic explanation of primary brain tumor development and coexisting molecular-genetic mechanisms. Frontal location of oligodendroglioma was suggested to be a favorable prognos‐ tic factor. The accumulated data clearly demonstrated that frontal location was strongly correlated with 1p19q deletion [92]. Prognostic variables in oligodendroglial tumors: a singleinstitution study of 95 cases. This translational information eased (helped) to predict the prognosis of these peculiar tumors. The embryological developmental basis of oligodendro‐ glioma and its molecular-genetic relationship are other issues, which require further investi‐ gation.

Lucius Annaeus Seneca, known as Seneca the Younger (c. 4 BC–AD 65), stated: "No one can wear a mask for very long." We can further apply this wise quote to our update neurooncological approach, which requires redefinition in the coming decades: "No tumor can wear a mask for very long." The molecular-genetic data and determining its relationship with primary brain tumors will further relieve "the mask" of the primary brain tumors. The upcoming new WHO classification of central nervous system tumors will consider this issue.
