As early as 2006, CCT6A was shown to play an important regulatory role in cancer[19]. Meng Zhu in 2017 found that low-frequency missense variants in the chaperone protein accompanying CCT6A were significantly associated with survival in patients with non-small cell lung cancer[20]. Klimczak M used the TCGA database to identify the overexpression of CCT6A in breast cancer as a significant contributor to poor prognosis[21]. In a study on colon adenocarcinoma, it was pointed out that high expression of the CCT6A promoted the growth of colon adenocarcinoma cells on the one hand, and was associated with low survival rate of colon adenocarcinoma on the other[22]. CCT6A also showed a strong association with survival and prognosis in renal cancer, with patients with altered CCT6A mRNA (stage I-IV) having significantly shorter overall survival compared to healthy controls[23]. In summary, the CCT6A gene plays a key role in the development of many tumors and affects prognosis. These are consistent with our research. Notably, in the present study, patients with high CCT6A expression had a lower survivorship probability than those with low CCT6A gene expression. In addition, most patients with EFS < = 5 years showed high expression of the CCT6A gene. These results suggest that patients with ES accompanied by elevated CCT6A gene expression levels may have a strong association with low survival probability and EFS < = 5 years. Another noteworthy point is that in our results on CCT6A gene expression under different subgroups, we found that the median gene expression level of CCT6A gene expression in patients in the metastatic group was much higher than the median gene expression of patients in the primary tumor group and the median gene expression of patients in the recurrent group. This suggests that there is a relationship between high expression of the CCT6A gene and tumor metastasis. It is well known that in most cases, metastasis of the tumor is a vital factor in the death of the patient[24]. Therefore, high expression of CCT6A may be accompanied by tumor metastasis and EFS < = 5 years. In other words, high expression of the CCT6A gene could serve as an important biomarker for the predictive prognosis of ES. If high expression of the CCT6A gene is detected in a given ES patient, it predicts a much lower SURVIVAL probability than in a patient without high CCT6A expression, as well as a high probability that the patient will have an EFS < = 5 years.
At the same time, the results of KEGG enrichment analysis and GO enrichment analysis corroborate our view. In this study, the KEGG enrichment analysis of differentially expressed genes was mainly distributed in the Cell cycle, DNA replication, Mismatch repair, cellular senescence and other pathways. As early as 2001, it was shown that the cell cycle in cancer, dysregulation of cell proliferation and a number of other factors together constitute the minimum required site for tumor development[25]. Research in DNA replication is also progressing, and its relationship to cancer development is becoming clearer. Dysregulation of DNA replication can lead to genomic instability, and an important feature of cancer formation is this instability[26]. Cancer may be related to errors in DNA at the replication stage and the combined effects of changes caused by environmental factors and mutations in genetic information[27]. The Mismatch repair pathway plays an important role in the study of many tumors[28],[29],[30]. Cellular senescence, which refers to a permanent state of cell cycle arrest, can lead to a decrease in the regenerative potential and tissue function of an aging organism, which can lead to tumorigenesis[31]. Another way in which aging promotes cancer progression is by promoting pathological cell proliferation[32]. The aforementioned KEGG pathway enrichment results indicate that the pathways enriched by the differential genes in this study are strongly associated with tumor cell initiation, development, and formation. In the GO enrichment analysis, CCT6A was mainly enriched in the DNA biosynthetic process pathway. It has been noted that acquired mutations or inheritance in major factors regulating DNA methylation can be observed in cancer[33]. We conjecture that the CCT6A gene likely promotes ES by regulating the DNA biosynthetic process. There are a total of 13 genes in the protein reciprocal network that are closely associated with CCT6A, and all 13 genes are very closely related to cancer. Among them, the CSE1L gene has been found to show a positive correlation between its high expression and high cancer stage and poor prognosis in cancer patients[34]. Meanwhile, the CCT2 gene has also been shown to reduce the survival rate of colorectal cancer patients with higher levels of gene expression[35]. Elevated expression levels of The CCNE2 gene coincided with shorter overall survival in patients with hepatocellular carcinoma[36]. Thus, the results presented by the network of protein interactions suggest that all of these genes linked to CCT6A are associated with the development of cancer.
The results of this study clearly show that the expression level of CCT6A presents high expression in ES patients, and high expression of CCT6A in ES patients is associated with poor prognosis. Differentially expressed genes in GO enrichment analysis are mainly distributed during DNA biosynthesis, DNA conformational changes, chromosomal regions, catalytic activity, and action on DNA. KEGG Pathway enrichment analysis was mainly enriched in Cell cycle, DNA replication, Mismatch repair, and cellular senescence pathways. The protein interaction network also suggests that all of these genes linked to CCT6A are associated with cancer development. In the survival curve, patients accompanied by high expression levels of the CCT6A gene had a much lower SURVIVAL probability than patients not accompanied by high expression levels of CCT6A. Patients with EFS < = 5 years all had high expression of the CCT6A gene. High expression levels of CCT6A have also been linked to tumor metastasis in ES patients. All of these results suggest that CCT6A can serve as a biomarker for ES and is an important gene for predicting prognosis.
This study analyzed gene table data and clinical data from a bioinformatics perspective only to derive biomarkers that correlate Ewing sarcoma with prognosis. There is also a limitation to our study: there is no experimental way to verify that the genes we arrive at are also consistent in the experiment.