Abstract:

Objective To analyze the relationship between the expression level of COMM domain-containing protein 7 （COMMD7） and prognosis of the brain low-grade glioma （LGG） patients by bioinformatics method， and to find new potential biomarkers of brain LGG， and to establish the prognostic prediction model，and to provide the basis for the prognostic prediction and individualized treatment of the patients. Methods A total of 523 brain LGG samples and 1 152 normal samples were downloaded from the UCSC Genome Database. Mann-whitney U test was used to analyze the expression difference of COMMD7 between brain LGG samples and normal samples. The Human Protein Atlas （HPA） Database was used to verify the results. DESeq software package of R language was used to screen the differentially expressed genes （DEGs） in the brain LGG samples in low expression of COMMD7 group and high expression of COMMD7 group； pROC software package of R language was used to perform the receiver operating characteristic （ROC） curve， univariate and multivariate Cox regression analysis were used to analyze the relationship between the COMMD7 expression and clinicopathological features of the brain LGG patients and its effects on the 1，3， and 5-year survival rates of the brain LGG patients； ggplot2 software package of R language was used to construct the forestplot； RMS software package of R language and survival package were used to construct the Nomogram and Calibration prediction model；the proportional risk regression model was used to analyze the diagnostic value of COMMD7 in distinguishing the brain LGG samples from normal samples. GEPIA and Oncolnc Databases were used to further verify the relationship between COMMD7 and prognosis of the brain LGG patients. Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis were used to analyze the function and pathway enrichment of the DEGs； Gene Set Enrichment Analysis （GSEA） was used to obtain the significantly enriched gene sets of DEG； TISIDB Database was used to analyze the correlation between the COMMD7 expression and immune cell infiltration of the brain LGG patients. Results The expression of COMMD7 in the brain LGG samples was significantly increased，and the HPA detection results showed that COMMD7 was highly expressed in the brain LGG samples. A total of 764 DEGs were identified （|log₂FC|>1， P<0.05）， including 654 up-regulated DEGs and 110 down-regulated DEGs.The predictive model based on the multivariate analysis results suggested that COMMD7 was an independent prognostic factor. The ROC analysis results showed that COMMD7 had a high diagnostic value in distinguishing the cancer tissue from the adjacent tissue ［area under curve （AUC） = 0.835， 95%CI = 0.816－0.853］.The Cox regression results showed that the survival rate of the brain LGG patients in high expression of COMMD7 group was significantly lower than that in low expression of COMMD7 group， and the high expression of COMMD7 was negatively related with poor prognosis of the brain LGG patients（P<0.01）. The analysis results of 514 LGG samples from GEPIA Database and 510 brain LGG samples from Oncolnc Database showed that the survival rate of the brain LGG patients in high expression of COMMD7 group was significantly lower than that in low expression of COMMD7 group （P=0.003， P=0.006）； the GO enrichment analysis results showed that the above DEGs were mainly enriched in the DNA-binding transcription activator activity， RNA polymerase Ⅱ-specificity， enhancer sequence specific DNA binding， and enhancer binding and so on； the KEGG enrichment analysis results showed that DEGs were mainly enriched in the transcriptional misregulation pathway in cancer. The GSEA results showed that DEGs were mainly enriched in the cell cycle in KEGG Database（N=1.950， P=0.012），cell cycle in World Press（WP） Database（N=1.944， P=0.012）， G₂ /M checkpoints （N=2.118，P=0.0012），and G₂/M DNA damage checkpoints （N=1.879， P=0.012）. High expression of COMMD7 was not only associated with stabilization of P53 closely realted to tumor（N=1.793，P=0.012），but also activating P53 downstream pathway（N=1.782，P=0.012），and p53 signaling pathway （N=1.762，P=0.012）， and activating Tp53 regulated transcription of cell cycle genes （N=1.766， P=0.018）.The immune infiltration analysis results showed that the expression of COMMD7 was significantly positively correlated with the numbers of 15 kinds of cells including activated CD8+T lymphocytes，central memory CD8+T lymphocyte and CD56^bright natural killer cells， and so on（P<0.05）， the expression of COMMD7 was significantly positively correlated with 11 kinds of key immune checkpoints including indoleamine 2， 3-dioxygenase 1 （IDO1）， galactin 9 （LGALS9）， and CD244， and so on（P<0.05），and the expression of COMMD7 was significantly negatively correlated with CD274 （PD-L1）， kinase insert domain receptor （KDR）， and T lymphocytes immunoreceptor with Ig and ITIM domains （TIGIT） （P<0.05），and the expression of COMMD7 was positively correlated with 4 kinds of key immune stimulators including CD40， CD276， and CD48，and 5 kinds of immune chemokines including C-C motif chemokine ligand 2 （CCL2），C-C motif chemokine ligand 5 （CCL5）， C-X-C motif chemokine ligand （CXCL9） and so on. Conclusion The high expression of COMMD7 may be a factor of the poor prognosis and a potential biomarker and therapeutic target of the brain LGG patients， and it can promote the occurrence and development of brain LGG by regulating the transcriptional misregulation pathway in cancer， activating p53 signaling pathway and the dysregulation of p53 downstream pathway related genes. COMMD7 may play a key role in the immune checkpoint inhibitor therapy in the brain LGG patients.

Key words: COMM domain-containing protein 7, Brain low-grade glioma, Bioinformatics, Prognosis, Immune infiltration