| Objective Tumor is a type of disease caused by changes in multigenes that lead to disorders both in cell cycle and cell growth.The cell cycle is regulated by a series of factors.Among them,cyclin D1(encoded by CCND1)is the factor most closely related to tumorigenesis and tumor development.Clinical data indicated that the amplification of CCND1 is not only an important factor for tumorigenesis and tumor development,but also a potential mechanism for primary resistance to immune checkpoint inhibitors(ICIs).The purpose of this study was to investigate prevalence of CCND1 amplification and its correlation with clinical efficacy of ICIs in solid tumors.Methods1.Samples diagnosed with solid tumor were obtained from The Cancer Gene Atlas(TCGA),Memorial Sloan-Kettering Cancer Center(MSKCC),Geneplus-Beijing databases.In three cohorts,the incidence of CCND1 amplification was determined.2.In TCGA and MSKCC databases,Kaplan-Meier and Cox regression analyses were used to analyze univariate and multivariate survival among patients with CCND1 amplification and patients with CCND1 neutral diploids.The significance of CCND1 amplification on the prognosis of solid tumor patients and correlation with clinical efficacy of ICIs were also explored.3.In TCGA,the immune integration algorithms called ESTIMATE,IIS and TIS were used to calculate the infiltration abundance of immune cells in tumor tissues among patients with CCND1 amplification and patients with CCND1 neutral diploids,respectively.The unpaired t-test method was used to compare the expression levels of immune function-related genes between the two groups.Gene Sets Enrichment Analysis(GSEA)was used to analyze the up-regulated genes in CCND1 amplification group.The immune effect of CCND1 amplification on tumor immune microenvironment(TME)and the expression of oncogenes were analyzed at transcriptome level.Results1.In three cohorts(n=27251),CCND1 amplification occurs in many cancer types,including esophageal cancer,head and neck squamous cell cancer(HNSCC),breast cancer,bladder urothelial cancer,with frequencies ranging from 9.63% to 34.78%.In the Chinese population,HNSCC,esophageal carcinoma,and bladder urothelial carcinoma are common,with frequencies ranging from 9.76% to 25.00%.2.We found that overall survival(OS)were no significantly different in the CCND1 amplification than that in the neutral group in the TCGA and MSKCC populations,(TCGA: Amplification group m OS:1838d,Neutral group m OS:2133d,HR:1.13,95%CI:0.96～1.32,P=0.13;MSKCC: Amplification group m OS:20.55 m,Neutral group m OS:25.44 m,HR:1.16,95% CI:0.93～1.46,P=0.15).Furthermore,in the MSKCC cohort,patients receiving ICIs with CCND1 amplification had a shorter OS compared with neutral patients(MSKCC: Amplification group m OS:11.0m,Neutral group m OS:18.0m,HR:1.63,95% CI:1.09～2.43,P=0.002).3.Transcriptome analysis in nine solid tumors from the TCGA cohort showed an up-regulated m RNA expression level of CCND1,oncogenes like PDGFB/PDGFRB、FGFR2、MET,immunosuppressive genes like TGFB、VEGFA、 ANGPT2、HIF1A and down-regulated m RNA expression level of immune cell-related genes in CCND1 amplification group compared with neutral group.The GSEA suggested that CCND1 amplification correlates with multiple aggressive,immunosuppressive hallmarks including epithelial mesenchymal transition,TGF-β signaling,KRAS signaling,PI3K/AKT-m TOR signaling,p53 pathway and hypoxia signaling in solid tumors.Conclusions1、CCND1 amplification is common in solid tumors such as esophageal cancer,HNSCC,breast cancer,and urothelial carcinoma in caucasian population.In the Chinese population,HNSCC,esophageal carcinoma,and bladder urothelial carcinoma are common.2、Our study indicates that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks,and it hinders not only the natural host immune responses but also the efficacy of ICIs in solid tumors.CCND1 amplification may be a potential mechanism for primary resistance to ICIs. |
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