The Role Of FOXM1 In Clear Cell Renal Cell Carcinoma For Overall Survival And Its Relationships With Immunity

Objective: Renal cell carcinoma is a common malignant tumor of urinary system,and the newly confirmed cases and deaths remain high every year.Renal cell carcinoma(RCC)accounts for90% of renal cell carcinoma and clear cell carcinoma(cc RCC)is the most common pathological type of RCC.The clinical manifestations of renal cell carcinoma are mass,low back pain,hematuria,etc.However,due to its hidden process,the proportion of patients with classic triad is less than 20%,and about one third of patients have metastasis at the time of diagnosis and often have poor prognosis.Patients with localized or locally progressive renal cell carcinoma(early or middle stage)are treated mainly by surgery.But patients with metastatic renal cell carcinoma(advanced stage)are treated mainly by radiotherapy,chemotherapy,molecular targeted therapy and immunotherapy.Although these treatments improve the prognosis of cc RCC,most patients still have no significant clinical benefits.Therefore,we need to pay more attention to the implementation of cancer precision medicine and explore new biomarkers and therapeutic targets of kidney cancer.FOXM1 is a member of the Forkhead Box transcription factor family.In recent years,many studies have confirmed that cc RCC is closely related to the proliferation of various human malignant tumor cells,but there are few reports about cc RCC at home and abroad.In this study,we hope to find the relationship between FOXM1 and clinical pathological parameters,immunity and disease prognosis by detecting the difference of FOXM1 expression between cc RCC and normal cells,and explore whether FOXM1 can find different potential targets for cc RCC,which provides more possibilities for early detection and treatment of cc RCC in clinical first line.The purpose of this study was to evaluate the value of FOXM1 in predicting the prognosis of cc RCC and determine the correlation between FOXM1 and immunity.Methods: We downloaded the data of cc RCC transcriptome from TCGA(The Cancer Genome Atlas)database,including related clinical information,and used “limma” software package to analyze the difference.The expression of cc RCC was further verified by real-time quantitative polymerase chain reaction(q RT-PCR)and immunohistochemistry.Univariate and multivariate Cox regression analysis were used to evaluate whether FOXM1 gene can be used as an independent prognostic factor of overall survival(OS)in cc RCC.Gene set enrichment analysis(GSEA)was used to identify the potential signal pathway of FOXM1.We analyzed the correlation between FOXM1 and microsatellite instability(MSI),Tumor mutational burden(TMB),Tumor neoantigen burden(TNB),Tumor microenvironment(TMC),Immune cells infiltration,Immune checkpoint molecules and Immune cells.Finally,we use the Cell Miner databaseto screen FOXM1 gene-related pathways and drugs,and we use the TIDE(Tumor Immune Dysfunction and Exclusion)database to predict the response of FOXM1 gene to immunotherapy.Results: Based on the data from the TCGA database,our results showed that FOXM1 expression in cc RCC was significantly elevated compared with normal paracancerous tissues,and the high expression of FOXM1 gene was closely associated with shorter OS.The results of q RT-PCR confirmed the high expression of FOXM1 in cc RCC,and immunohistochemistry confirmed the positive expression of FOXM1 in cc RCC.The results of correlation analysis between FOXM1 and clinicopathological factors showed that there was a significant correlation between FOXM1 expression level and grade,M stage,N stage,stage,T stage and race(white and African),but there was no significant relationship between age,sex and race(African and Asian)and FOXM1 expression.The results of univariate and multivariate risk regression analysis proved that FOXM1 was a stable independent prognostic factor.Further application analysis of GSEA showed that FOXM1 played a role through six signaling pathways: cell cycle pathway,chemokine signaling pathway,JAK-STAT signaling pathway,NOD-like receptor signaling pathway,P53 signaling pathway and T cell receptor signaling pathway.The expression of FOXM1 was also significantly correlated with MSI,TMB,immune cells,immune checkpoint molecules,tumor microenvironment and immune cell infiltration.We further predicted the response of FOXM1 gene to immunotherapy through IMvigor210 cohort and TIDE database.The analysis results of Cell Miner database showed that FOXM1 expression was positively correlated with 5-fluoro deoxy uridine 10 mer drug and Triapine drug.Conclusion: The elevated expression of FOXM1 gene is associated with poor prognosis in cc RCC patients and could be an independent prognostic factor of cc RCC.At the same time,we also found the signal pathway regulated by FOXM1 in cc RCC and its relationship with immunity,which will hopefully bring new targets and more evidence for the treatment of ccRCC.