NOTCH proteins are a family of type-1 transmembrane proteins, forming a core component of the signaling pathway. NOTCH proteins appear to act as transmembrane receptors for intercellular signals; the known are: NOTCH1, NOTCH2, NOTCH3 and NOTCH4 [69].NOTCH signal activation depends on direct interaction of one of the four NOTCH receptors (NOTCH1–4); particularly, ligand-induced proteolysis of NOTCH receptors release the NOTCH intracellular domain that control the expression of a wide range of specific target genes, suggesting its multiple functions, including cell proliferation, stem cell maintenance, cell fate decisions and differentiation [70].The NOTCH signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells. It represents a critical regulator of differentiation programs; influencing cell cycle kinetics and apoptotic signals, it can be suggested that NOTCH proteins may be involved in the malignant transformation of selected cell systems. Alterations in NOTCH signaling are visible in various disease [71]. Interestingly, the most common inherited cause of stroke and vascular dementia in adults are represented by a genetic mutation NOTCH3 gene; particularly, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) symbolizes the genetic mutation in the neurogenic locus of NOTCH3 gene [72,73].Numerous evidence shows NOTCH participation in carcinogenesis and human tumors. NOTCH activation has been mainly associated with its multiple effects in sustaining oncogenesis, including tumor cell proliferation, migration, cell cycle progression and apoptosis inhibition [74,75]. Due to its pleiotropic function, the NOTCH signaling pathway is involved in many aspects of tumor development and may act as either an oncogene or a tumor suppressor. The balance between one role and another is determined by many different factors [76]. Indeed, NOTCH signaling is constitutively activated in several types of cancer cells, acting as an antiapoptotic or pro-oncogenic signal. NOTCH3 overexpression has been reported to be responsible for increased in vitro tumor cell growth in human lung cancer and NOTCH3 constitutive activation was reported to inhibit terminal differentiation in lungs of transgenic mice. Moreover, increased expression of NOTCH3 has been observed in human tumors and also participates in the induction of terminal differentiation and growth arrest [77]. Excitingly, different mutation clusters within the NOTCH1 receptor gene significantly encourage tumor progression by causing a ligand-independent constitutive activation of the pathway [78]. Brain cancer data in The Cancer Genome Atlas (TCGA) (https://www.cancer.gov/) were downloaded from cBioPortal for cancer genomics, including gene expression profiles of NOTCH genes and clinical information, observing an increasing variance incidence predominantly for NOTCH1. Notably, NOTCH signaling hypothetically controls multiple steps of gliomagenesis, comprising tumor initiation, progression and recurrence, although a clarified involvement of NOTCH in glioma development is still missing. Furthermore, NOTCH signaling plays a central role in maintaining the quiescent NSC pool [79], which result to be resistant to treatment and can regenerate proliferating progenitor cells. As well, NOTCH signaling activity can increase stem cell features, supporting resistance to radio- and chemo-therapies and activating oncogenic pathways or inhibiting tumor suppressor. On the other hand, NOTCH-inactivating mutations and low expression levels of canonical NOTCH target genes have been documented in patients with glioma, indicating a tumor-suppressive role of NOTCH. The data obtained using cBioPortal for cancer genomics allowed us to analyze the frequency of mutations in NOTCH genes, providing e a model of gene interaction to be studied in depth in the pathogenesis of brain cancer (Figure 2). Among various epigenetic alterations, such as acetylation, phosphorylation, ubiquitylation and sumoylation, promoter region methylation is considered as an important component in cancer development. Various studies have shown that DNA methylation is reversible, and demethylating drugs can reverse the silencing of genes resulting from methylation. Regarding NOTCH genes, not much is known about the methylation status in cancer. Interestingly, brain cancer data in The Cancer Genome Atlas (TCGA) (https://www.cancer.gov/) downloaded from cBioPortal for cancer genomics, highlighted an increasing methylation status (HM450) predominantly for NOTCH3, compared to other NOTCH genes, as shown in Figure 3. Deletions or shallow deletions were corresponding to lower mRNA expression, while copy number gains or amplifications were linked to increased mRNA expression of the NOTCH genes. The shallow deletions of NOTCH1 and NOTCH2 are the most frequent copy number loss of these NOTCH genes, while the gain of NOTCH3 and NOTCH4 DNA copy number represents the most common change in gene amplification (Figure 3). A better confirmation of the role of glioma in the involvement of the NOTCH gen, is shown by analyzing the NOTCH pathway in glioma downloaded from cBioPortal for cancer genomics, highlighting that 7.4% of glioma patients show a mutation in NOTCH1 gene (Figure 4). Interestingly, a combined study on NOTCH gene mutations in glioma and GBM and patient’s survival (data obtained from cBioPortal) highlighted that the patient’s survival was lower in patients with NOTCH4 mutations (11 months) and NOTCH3 (13 months) compared to NOTCH1 (77 months) and NOTCH2 (19 months). Also, patients with double mutations in NOTCH3/NOTCH4 showed a reduced survival (18 months) compared to double mutations in NOTCH1/NOTCH2 (57 months) (Figure 5).