The Cholesterol Synthesis-related Molecular Classification And Prognostic Risk Model For Hepatocellular Carcinoma

Background and objective:Hepatocellular carcinoma(HCC),the main cause of cancer-related death.has the dysregulation of lipid metabolism which affects the development of HCC.The study aim to analyze the expression,gene mutation and copy number variation of cholesterol synthesis-related genes in HCC,establish molecular classification and prognostic risk model for HCC based on the expression of cholesterol synthesis-related genes,and investigate the clinical significance and potential mechanism of the molecular classification and prognostic risk model.Methods:From The Cancer Genome Alters(TCGA)database and the International Cancer Genome Consortium(ICGC),we collected the transcriptome data,gene mutation and copy number variation data as well as corresponding clinical survival pathological information of HCC patients,and eligible patients were screened.Genes related to human cholesterol synthesis were collected from the BioCyc genome database.The expression levels and gene copy number variation of cholesterol synthesis-related genes in tumor tissues were analyzed.The waterfall plot of somatic mutation showed gene mutation about cholesterol synthesis.Consensus Clustering analysis was used to identify molecular classification of hepatocellular carcinoma based on cholesterol synthesis-related genes.The difference distribution of subtypes was analyzed by principal component analysis(PCA).Clinical significance of molecular subtype was analysed by survival analysis and clinical characteristic analysis.The single sample gene set enrichment analysis(ssGSEA)was utilized to the KEGG pathway between subtype.The xCell algorithm was used to analyze tumor cell types distribution in subtypes.We identitied he best prognostic genes from cholesterol synthesis-related genes by least absolute shrinkage and selection operator(LASSO)Cox regression analysis and builded a prognostic risk model based on it.According to the optimal cutoff value,the patients were divided into high-risk group and low-risk group.Survival analysis evaluated the clinical significance of the prognostic model,and the predictive power of the model was evaluated by Receiver Operating Characteristic(ROC)and The Area Under the Curve(AUC).ICGC data were used to verify the reliability of the prognostic risk model.the analysis of differential expression,GSEA,gene mutation,and immune cell infiltration was used to investigated the possible mechanisms of the prognostic model.The concordance index(C-index),ROC curve and AUC were used to verify its robustness and predictive ability of the nomogram constructed by prognostic risk model and tumor stage.Results:The expression level and copy number variation of cholesterol synthesis-related genes in HCC tissue is abnormal.The gene mutation frequency of cholesterol synthesis-related genes is low.A molecular classification of hepatocellular carcinoma was identified by Consensus Clustering analysis,which contained three subtypes.the HCC patients in Subtype 3 had the worst prognosis and showed clinical characteristics of advanced HCC.Type 3 is enriched in cell cycle and cancer-related signaling pathways and is associated with immune infiltration.Subtype 1 and Subtype2 was enriched in metabolic correlated pathways.Seven genes with the best prognosis were screened by LASSO regression analysis,which were ACAT1,HMGCS2,GGPS1,FDPS,LBR,NSDHL and DHCR24.A prognostic risk model was constructed based on cholesterol synthesis-related genes by LASSO and multic Cox regression analysis.In this model,the survival of patients in the high-risk group was significantly worse than that in the low-risk group.The potential mechanism is that the high-risk group has more malignant phenotypic pathways related to cell proliferation and growth,and high tumor mutation load,and the mutation frequency of the tumor suppressor gene TP53 in high-risk group is high.In addition,the high-risk group showed more immune cells,especially mmunsupressive cells.The expression of inhibitory immune molecules was higher in the high-risk group than in the low-risk group.Prognostic model is an independent prognostic factor,and the combination of prognostic risk model and tumor staging was utilized to construct a nomograph which has reliability and important clinical significance.Conclusion:The alteration of the transcription pattern of cholesterol synthesis-related genes in HCC may be partly due to the change of its copy number variation.The cholesterol synthesis-related molecular classification and prognostic risk model have the important clinical significance,and reveal that cholesterol synthesis plays an important role in the progression,metabolic changes and immunophenotype of HCC.