Relationship Between Spindle Microtubule Kinesis Associated Genes And DNA Repair Genes And Cancer Risk

Object: SKA complex and KMN network key proteins,as important components of the connection between spindle microtubules and kinetocytes,participate in the mitotic process of eukaryotes and mediate the occurrence and development of a variety of tumors.The SKA complex is composed of three subunits SKA1,SKA2 and SKA3,and the key proteins of KMN network are regulated by NDC80,KNL1,MIS12,NUF2,SPC24 and SPC25,.The abnormal expression of these key proteins is closely related to the occurrence and development of tumor,but the specific mechanism of participation in breast cancer is unclear.Therefore,we systematically bioinformatics to study the expression of key genes in spindle and kinetocyte binding complex(SKA)and KMN network(MIS12-NDC80-KNL1)in breast cancer and its molecular subtypes,as well as its relationship with breast cancer and correlation between prognosis of cancer.Systematic bioinformatics and meta-analysis were used to explore the expression level of DNA damage repair related gene mRNA and the correlation between candidate polymorphic SNP locus and tumor risk.Methods: In this study,the mRNA expression and DNA mutation of SKA complex and KMN network related genes in tumor were analyzed by oncomine database and cBioPortal database.The correlation between the above genes and the prognosis of cancer patients was analyzed by PRECOG database.The correlation between them is analyzed through the String database.Then we use TCGA database to analyze the expression of the above related genes in breast cancer patients and normal patients,as well as their co-expression genes.in the next step,we use DAVID to analyze the gene function annotation of the co-expressed genes.And we used Breast cancer geneexpression miner v4.1 database to analyze the mRNA expression of these genes in different types of breast cancer,such as patient age,receptor status,lymph node metastasis,breast cancer molecular subtypes and so on.Finally,we analyzed the effect of high and low expression of candidate genes on recurrence-free survival(RFS)and distant metastasis-free survival(DMFS)in patients with breast cancer by Kaplan-Meier curve.The expression of DNA repair gene in tumor was analyzed by Oncomine and GENT database.The prognostic mutations of DNA repair genes in tumors were analyzed by PRECOG database.Then,the mutation of DNA repair gene in tumor was analyzed by cBioPort database.Finally,meta-analysis was used to explore the relationship between single nucleic acid mutation of DNA repair gene and cancer risk.Results: 1.Based on Oncomine platform,it was found that SKA complex,NDC80 complex and KNL1 related genes were significantly highly expressed in breast cancer and other tumors.Only MIS12 was low expressed in breast cancer and other tumors.At the same time,on the cBioPortal platform,it was found that the mutations of SKA1,SKA2 and SKA3 genes were very low,and had little correlation with the high expression in tumors.Finally,the Z-SCORE value was calculated by PRECOG website,and the effect of these genes on the prognosis of tumor patients was systematically analyzed.it was found that the mRNA expression of other genes except MIS12 gene was related to the shortening of the overall survival time of patients.2.Through TCGA database,the results showed that in addition to MIS12 gene,the other genes were highly expressed in breast cancer,and there was statistical significance(P < 0.05),and through co-expression analysis,it was concluded that the other genes were highly expressed in breast cancer(P < 0.05).It was found that they were all related to mitosis,cell cycle and cell division of breast cancer.3.Using Breast cancer gene-expression miner v4.1 database,it was found that the mRNA expression levels of SKA complex,NDC80 and KNL1 related genes were closely related to the phenotype of breast cancer.The expression of breast cancer in the three negative type was higher than that in the non-three negative type(P < 0.05),and the expression in the basal type was higher than that in the non-basal type(P < 0.05),the expression of),SBRIII breast cancer was the highest,SBRII breast cancer was the second,and SBRI breast cancer was the least.4.Kaplan-Meier Log-rank test showed that the high expression of SKA complex,NDC80 complex and KNL1 related genes was significantly correlated with the shortening of RFS and DMFS(P < 0.05).5.In 33 kinds of tumors,such as breast cancer,colorectal cancer and ovarian cancer,abnormal low expression of XPA and XPC was found,while abnormal high expression of XPD,WRN and XPF was found.prognostic analysis showed that the low expression of XPA and XPC was associated with the prolongation of overall survival time of patients with breast cancer,colorectal cancer and ovarian cancer.The high expression of XPD,WRN and XPF was associated with the shortening of the overall survival time of tumor patients.6.A total of 58 studies were included in Meta analysis.it was found that XPArs10817938 CC genotype and XPDrs238406 AA genotype significantly increased the risk of tumor patients,while XPFrs3136038 xxx genotype decreased the risk of tumor patients.But in stratified analysis,the XPArs2808668 CC genotype reduced the risk of cancer in patients with tumors other than digestive system tumors.Moreover,WRNrs1346044 CC genotype and WRNrs1801195 TT genotype significantly increased the risk of breast cancer and reproductive system tumor,respectively.XPC rs1870134 was not associated with the risk of tumor.Conclusion: 1.Spindle-kinetomere related genes SKA1,SKA2,SKA3,NDC80,KNL1,NUf2,SPC24 and SPC25 are highly expressed in many tumors,especially in breast cancer,indicating that they are closely related to the occurrence of breast cancer.2.The expression of candidate genes is abnormally high in breast cancer with molecular subtype three negative and basal breast cancer,and is positively correlated with high SBR stage,indicating that it is associated with the malignant degree of breast cancer and the pathological process of patients.3.Through the survival analysis of SKA complex,NDC80 complex and KNL1 related genes in breast cancer,we found that the high expression of mRNA,except MIS12 gene,was associated with the shortening of RFS and DMFS in patients with breast cancer.It is suggested that it can be used as a molecular marker to evaluate the prognosis of breast cancer.4.According to the bioinformatics analysis of 33 kinds of tumors,according to GEO data set,the expression of XPA and XPC mRNA decreased,while the expression of XPD,XPF and WRN increased.The prognostic analysis of Meta Z score showed that the low expression of XPA or XPC could prolong the survival time of the patients,and the high expression of XPD,XPF and WRN was associated with the prolongation of the prognosis of the patients.Meta analysis showed that carrying XPA rs10817938 and XPD rs238406 was significantly associated with overall tumor risk,but in the overall cancer analysis,XPA rs2808668 excluded digestive system and XPF rs3136038 polymorphisms significantly reduced tumor susceptibility.In addition,the SNP of XPC rs1870134,WRN rs1346044 and rs1801195 was not associated with tumor risk.These results provide basic data and related support for the study of the regulatory mechanism of DNA damage repair related genes involved in tumorigenesis and development.