Constructing A Cellular Senescence-related Risk Score Model For Predicting Prognosis In Colon Cancer Patients

Objective Cellular senescence,defined as the permanent arrest of cell proliferation,is recognized to be involved in the progression and migration of tumor growth.However,senescent cancer cells can not only induce surrounding cell carcinogenesis through senescence associated secretory phenotypes(SASP)but also attract immune cells to kill tumor cells through SASP.Therefore,cellular senescence is considered a potential marker for cancer prognosis prediction and treatment.We designed to structure a cellular senescence-related risk score model based on cellular senescence-related genes for predicting prognosis in colon cancer patients.Methods The colon cancer datasets were sourced from two public databases.Senescent genes(Sn Gs)were extracted from the Cell Age database.According to the expression of Sn Gs,colon cancer patients were separated into different clusters.The differences in survival and differences in immune infiltration levels of patients among the different clusters were compared.Then,differential genes(DEGs)among clusters were extracted.This was followed immediately by univariate prognosis analysis of the DEGs and further screening for prognosis-related DEGs.The prognosis-related genes identified were used to establish a cellular senescence-related risk score model.In the next step,the data were categorized into either the high-risk or low-risk group depending on the medium of the risk score.The survival differences,differences of response to chemotherapeutic drugs and differences of response to immunotherapeutic drugs between the two subgroups were compared.Additionally,there was a nomogram which was developed to forecast the overall survival of individuals with colon cancer.Finally,DEGs between different risk score groups were extracted,and further DEGs between different score groups were extracted to calculate the top 10 key DEGs between the two groups,which were intersected with the Sn Gs.The intersected genes obtained were identified prognostically.Results Expression of 258 Sn Gs was extracted in this study.Patients affected by colon cancer were separated into three clusters(Cluster A,Cluster B and Cluster C)based on the expression level of these 258 Sn Gs.The patients in the three clusters exhibited obvious survival distinctions,with patients in clusters A and B having a better prognosis than those in cluster C.However,the patients from Cluster C showed significantly higher levels of immune infiltration when compared to those from Cluster A and Cluster B.A total of 2334 DEGs were selected across the three clusters,from which 681 DEGs were correlated with the clinical outcomes of individuals with colon cancer.These were then further filtered to obtain nine genes(FITM2,APOL6,VWF,PRRX2,CCL22,ALPL,SON,KIF7,and ZEB1-AS1).Therefore,a cellular senescence-related risk score model containing the nine genes was developed and colon cancer patients were classified into two groups.The clinical outcomes of individuals in the low-risk score group were proved to be significantly better.In addition,we constructed a nomogram with various variables.The nomogram displayed significant high accuracy when used to predict the survival rates of patients with colon cancer at one year,three years and five years.The effectiveness of the model in predicting patients’ survival was further validated in different clinical subgroups(male patients group,female patients group,age less than or equal to 65 years group,age more than 65 years group,T-stage group,N-stage group,M-stage group and TNM stage group).Moreover,the model also predicted distant metastases in colon cancer(AUC=0.670).A lower sensitivity threshold was found for patients with lower risk scores for the standard chemotherapy drugs oxaliplatin and5-Fluorouracil.In contrast,patients with high-risk scores had a greater potential for immune escape when treated with immunotherapy.Finally,two critical cellular senescence genes(FOS,MMP9)associated with colon cancer prognosis were identified between the high and low-risk score groups.Conclusion Patients with colon cancer can be classified into different clusters with significant prognostic differences based on cellular senescence-related genes.A risk score model was developed based on nine differential genes among clusters.It plays a predictive role in the prognosis,chemotherapy and immunotherapy responses of colon cancer patients.FOS and MMP9 are key genes for cellular senescence and are associated with prognosis in colon cancer.