| Background and Objective: Hepatocellular carcinoma(HCC)is a highly heterogeneous disease with clinical and molecular characteristics.Despite rapid development of diagnostic methods and treatment strategies,hepatocellular carcinoma is highly heterogeneous,making prognostic prediction and treatment selection extremely challenging.The development of bioinformatics has greatly promoted the understanding of the occurrence and development of hepatocellular carcinoma,and the derived results may promote the realization of accurate prediction and precision medicine in clinical practice.A systematic description of gene mutations and transcription in hepatocellular carcinoma will help to determine the mechanism of tumor progression,optimal treatment,and more accurate prognostic methods.TP53 is one of the most common mutated genes in hepatocellular carcinoma.It is of great clinical significance to stratified patients according to the mutation status of TP53,and then tailor specific prognostic prediction methods and treatment plans.The main objective of this study was to describe the mutation of the main driver gene of hepatocellular carcinoma,to develop a specific prognostic method for patients with wild type of TP53 hepatocellular carcinoma and to explore more personalized treatment options.Methods: Whole exome sequencing(WES)was performed on tumor biopsy samples from 125 hepatocellular carcinoma patients and baseline clinical and survival information was collected.Main mutated genes were identified by combining whole exome sequencing data from public databases,and correlations between main mutated genes and important clinical features were analyzed in our sequencing cohort.At the same time,we searched hepatocellular carcinoma samples with whole exome sequencing data and transcriptome sequencing data from public databases to further explore the immunological and biological characteristics related to TP53 mutation and LRP1 B mutation.Considering that the mutation status of TP53 is closely related to the disease development and prognosis of patients with hepatocellular carcinoma,we stratified patients with hepatocellular carcinoma according to the mutation status of TP53,and constructed a prognostic model for patients with wild-type hepatocellular carcinoma of TP53.Based on the risk score of the prognostic model,we divided the patients with wild-type hepatocellular carcinoma of TP53 into high risk group and low risk group,and further explored the biological and immunological differences between the high and low risk groups.Finally,we explored the practical clinical application of this prognostic model.Results: A total of 14 main mutated genes(TTN,TP53,OBSCN,APOB,ADGRV1,XIR P2,PCLO,CSMD1,USH2 A,LRP1B,FAT3,CSMD3,RYR2 and HMCN1)were identified by whole exome sequencing and retrieval of public databases.It was also found to be closely related to tumor stage(TNM stage),serum alpha-fetoprotein(AFP)level,maximum tumor diameter and other important clinical characteristics of hepatocellular carcinoma.Consistent with the results of previous studies,TP53 mutations and LRP1 B mutations in our whole exome sequencing cohort were also closely related to the prognosis of patients,and there were significant differences in biological and immunological characteristics between the mutant group and the wild group.For patients with wild-type hepatocellular carcinoma of TP53,we proposed a prognostic risk model based on 11 genes(NT5C1A,FAM163 A,DAPL1,SI,GABRA4,PCDHGB4,TLX3,HEMGN,CTSG,C15orf43,SERPINB5).According to the median risk score of the model,patients with wild-type hepatocellular carcinoma of TP53 were divided into high-risk and low-risk groups,and significant transcriptomic changes in metabolism-related pathways and immunological features were observed between the two groups,suggesting a predictable response of the model to immunotherapy for hepatocellular carcinoma.Finally,we constructed a multifactor profile for prognostic prediction in wild-type TP53 patients,and screened a small molecule drug(AM580)with precision therapeutic significance for high-risk patients.Conclusions: In this study,the molecular,biological and immunological characteristics of hepatocellular carcinoma were comprehensively revealed through whole exome sequencing,combined with whole exome sequencing data and transcriptome sequencing data in the public database.In addition,we present for the first time a prognostic model for patients with TP53 wild-type hepatocellular carcinoma.This model can stratify the risk of TP53 wild-type patients and accurately predict the survival state of patients,with a high degree of sensitivity and specificity.For patients with high model risk scores,our study provides them with a multifactor predictive prognostic profile and potential small-molecule therapeutics that may improve their prognosis in the most effective way.Significance: We identified main mutated genes that represent a broader range of hepatocellular carcinoma patients by combining whole-exome self-testing cohorts with multiple sequencing cohorts in a public database.At present,the development of prognostic models for hepatocellular carcinoma is mainly based on the whole population and TP53 mutant patients,which has the disadvantages of “one size fits all” and small scope of application.In addition,the average mutation frequency of TP53 in hepatocellular carcinoma is only 30%,and the construction of a prognosis model for wild-type patients with TP53 may benefit the majority of patients with hepatocellular carcinoma.Overall,these results require accurate prognostic prediction for patients with hepatocellular carcinoma with similar biological patterns,and provide new insights into the goal of clinical precision therapy and stratified care. |
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