Collection of genes related to brain cancerAccording to statistics, brain cancer has been one of the deadliest diseases in recent years. There is a lot of bioinformatics and clinical research about brain cancer especially the treatment so finding the group of genes that have a main role in brain cancer (driver genes) can lead to treatment and prevention. Collecting genes, they were noted in literature by CORMINE medical database (https://www.coremine.com/). In the COREMINE DB, all Brain cancer-related genes have been identified, and sorted based on their p-value. A threshold of 0.05 for the p-value criterion was used to select the significant genes. The selected genes list is included in the Supplementary file.Make a PPI networkNodes of the PPI network are 1385 proteins that related with selected genes in the previous step. The STRING database is a biology database of known and predicted protein–protein interactions that determine all kinds of physical and functional structures between proteins along processes connection interactions. In the setting of the STRING database, different confidences are available for building the PPI network, and the selection of each one determines the number of edges in the network. We have used a confidence score of 0.4, which is the default value of the STRING database, in order to ignore worthless connections on the one hand, and not to miss important information on the other hand. From the STRING setting, select physical and functional with the confidence of 0.4 which include 39,688 protein–protein interactions.Degree centrality analysisSince the set of vertices with a high degree has many connections, and thus a large number of neighbors, the degree centrality criterion was used in the PPI network. Therefore, the obtained hub proteins can be effective on many proteins in the network, which are important proteins related to brain cancer based on the literature. The degree centrality of nodes in the PPI network accrues when a node has lots of communication with other proteins and it has a high effect on the other neighbor nodes. 25 proteins with the highest degree are selected as hub proteins, which is specified in the list of proteins in Table 1.Table 1 4 out of 10 modules contain hub genes.Specify the most important moduleThe module is one of the subsections of the network that has high interconnection and low intra connection. The importance of the module is because the genes and proteins are located in a module have the same biological process. Based on this, the PPI network from the STRING database is divided into 10 modules using k-means clustering. 6 of the 10 obtained modules they do not contain hub proteins and are not reported in Table 1. According to the table, the sixth and ninth modules contain the most hub genes. But the number of vertices of the sixth module is high and the number of vertices of the ninth module is low. Therefore, the ratio of the number of hub proteins to the total proteins of the ninth module is greater compared to the sixth module, and therefore the ninth module is statistically more important. In the following, the edges of module 9 are oriented and controllability analysis has been done.Nineth module orientationBased on the method used in Ref.18, for the orientation of PPI networks, in which the direction of the edge between two proteins is considered from a protein with a lower degree to a protein with a higher degree18, ninth module has oriented and this module is designed to controllability analysis and to identify driver vertices.Checking the controllability and driver vertices selectionIn the previous parts, by analyzing the identification of hub vertices and modulation of the network obtained from the STRING database, it was determined that ninth module play a significant role in the formation and progression of brain tumors. Therefore, this module is oriented according to the method explained in the previous step, and then by analyzing the controllability of complex networks, the driver proteins of this module were obtained that if they are influenced by external signals, they can hierarchically control the entire vertices of the network19,20. The structural controllability proposed by Lin considers simplification based on which the system should have a directed network and be based on a structural matrix21 (in which only the presence or the absence of the edges is considered and the additional parameter specifying the weight of the edges is ignored). In this context, the minimum input theorem bases its investigation into the controllability of complex networks on the maximum matching, in which the unmatched vertices are considered as the driver vertices20, and has many applications22,23,24,25,26,27. Based on this, the control power of each vertex in the network is determined based on the set of vertices under its control, in other words, vertices in the network that have the most set of vertices under control have the highest rank based on the analysis of centrality of control27,28. 5 proteins (CD24, CXCR4, AXL, ANGTP1, BSG) have been identified as driver proteins in ninth module in Fig. 2.Figure 2Driver proteins in ninth module.In the following, the importance and effectiveness of identified hub and driver genes in the formation and progression of various cancers have been investigated and the various biological pathways that play a role in it have been mentioned. The description of the hub proteins mechanism is listed in Table S.1, and mechanisms of the driver proteins are provided below. Also, analysis of the expression data for the obtained driver genes has been done. For this purpose, 50 glioblastoma cancer samples and 20 normal bone marrow samples were used. The box plot of the expression level of driver genes in two groups obtained based on the eDAVE database29 is presented in Fig. S.1, Results show the different expression levels of driver genes in two groups.BSGBSG has a potential role in the prognosis and treatment of various metastatic cancers such as non-small cell lung cancer, prostate cancer, digestive tract cancer, liver carcinoma30.AXLAXL is a member of the family of receptor tyrosine kinases that plays a multifaceted role in promoting immune suppression and resistance to anti-tumor immunity and is effective in controlling the genetic programs of epithelial-mesenchymal transition. Also, this gene is involved in tumor progression, and metastasis. The extensive role of AXL in tumor biology is the reason why this gene is a candidate as a therapeutic target and anticancer drug. AXL signaling to Cancer cells helps to escape from immune surveillance. In fact, cancer cells use the AXL pathway to identify toxic environments and activate molecular mechanisms. This gene is found in cancers such as non-small cell lung cancer, cervical cancer, and colon cancer. Leukemia, squamous cell carcinoma of the head and neck, glioblastoma, and triple breast cancer are involved31.ANGTP1By binding to the endothelial cell membrane, tyrosine kinases play an important role in vascular growth and angiogenesis. ANGTP1 participates in various cancer processes, for example, the overexpression of this protein in mice gene spreads the tumor cells and the creation of metastasis32. Also, ANGTP1 is a potential therapeutic target and one of the regulators of angiogenesis in EC (Endometrial carcinoma) cancer33.CXCR4This gene is not only involved in more than 23 primary cancers such as kidney, ovarian, thyroid, breast, lung, colon and prostate cancer, but also in metastasis and stem cell cancer34. Also, this protein is involved in non-invasive monitoring, disease progression and therapeutic intervention is targeted35.CD24Several studies confirm the role of the this gene in the formation and progression of various types of cancers, including: Recently the CD24 gene has been described as an innate immune checkpoint with apparent importance in several types of solid cancers36,37. CD24 is usually accompanied by a more aggressive course of widely used as an indicator38. CD24 has been observed in many gene profiling analyses and may regulate cancer cell proliferation and invasion39. Downregulation of CD24 prevents proliferation and induction of apoptosis in tumor cells, while increased expression of CD24 increases tumor growth and metastasis40.Drugs that are effect on the driver genesAccording to the DGIdb database, medicinal compounds related to the obtained driver genes have been identified. For 4 out of 5 genes, there are different medicinal compounds. Medicinal compounds with the interaction score (IS) greater than 5, are specified in the Table 2.Table 2 Efficacious drugs on the identified driver genes.
