Integrating Multi-omics To Analyze The Perturbations Of TRIM Proteins In Malignant Tumor And The Regulation Mechanism Of Immunotherapy

Background: The tripartite motif(TRIM)proteins with highly conserved structures function as important regulators in innate immunity,tumorigenesis,cell differentiation and ontogenetic development.However,we still lack systematic knowledge about the genetic and transcriptome alterations landscape of TRIM proteins and their function about immune regulation across cancer types.Objectives: In this paper,in order to analyze the genetic and transcriptome alterations of TRIM protein family in various malignant tumors,we comprehensively reviewed and characterized the disturbance of TRIM genes in more than 10,000 samples of 33 cancer types.Through the systematic analysis of genetics and transcriptomics of TRIM genes in a variety of human tissue development and cancer,the genetic alterations and immune regulation functions of TRIM family are revealed,and a comprehensive insights and valuable data resources are provided for guiding the mechanism and therapeutic analysis of TRIM genes in cancer.Methods: The genome and transcriptome data of cancer patients were downloaded from The Cancer Genome Atlas(TCGA)database,which contains about10,000 samples of 33 cancer types.Based on the collected genetic alterations information,we systematically analyzed the mutation landscape of TRIM family,and identified the mutation-riched domains in TRIM proteins using ROI-Driver method.Next,differential expression analysis was performed using transcriptome data to explore the expression pattern of TRIM family.In addition,based on the expression of TRIM proteins in each sample,we calculated a index named TRIMs enrichment score(TRIMs score)using single-sample gene set enrichment analysis(ss GSEA)algorithm.Then,gene set enrichment analysis(GSEA)was applied to investigate the relationship between TRIMs score and cancer or immune-related pathways.By evaluating the correlation between TRIMs score and immune-related indicators such as immune cell infiltration and immune regulatory factors,we investigated the immune regulatory function of TRIM family.Finally,the TRIMs score as a feature was applied for survival analysis to explore the relationship between TRIM family and clinical survival rate of patients.Furthermore,the drug treatment data was obtained to investigate the relationship between TRIMs score and drug treatment response of cancer patients,which contributed to understand the potential value of TRIM family about cancer therapy.Results: The results suggest that alterations in TRIM gene and protein levels frequently emerge in a wide range of tumors.In particular,the somatic mutations located in TRIM protein domains are likely to be deleterious mutations.We have identified seven potential driver mutation genes through ROI-Driver method,such as TRIM16,TRIM4,TRIM43,TRIM67,TRIM7,TRIM72 and TRIM73.Mutations of TRIM16 are mainly concentrated in the SPRY domain.The coiled coil region is the mutation-enriched domain for TRIM4 and TRIM43,while PRY domain is for TRIM7 and TRIM72.The mutations of TRIM73 are enriched in the RING domain,and the mutations of TRIM67 are enriched in the fn3 structure.In addition,TRIM family has widespread transcriptome alterations in cancer,and most TRIM genes are differentially expressed in at least one cancer.Compared with normal samples,some TRIM genes,such as TRIM28 or TRIM58,showed generally increase or decrease expression in various cancers.Perturbations of TRIM genes are significantly correlated with expressions of immune checkpoints and immune cell infiltration,which further regulated the cancer-and immune-related pathways,such as interferon response pathways and epithelial-mesenchymal transition pathway(EMT).Furthermore,we propose the TRIMs score strategy,which can accurately predict the clinical outcome of cancer patients.In a variety of cancers,TRIMs scores of patients are correlated with clinical survival and immune therapy response across cancer types.In HNSC,LGG,LUAD,PCPG,COAD,CHOL,PAAD,KICH,TGCT,DLBC,THYM and SKCM,TRIMs score tends to be the risk factor,and is associated with poor survival.TRIMs score is more likely to be a protective factor,and the higher TRIMs score is significantly related to the survival rate of patients in UVM,MESO,ACC,THCA,ESCA,READ,STAD,BLCA,KIRC,KIRP,CESC and SARC.In melanoma treated with anti-PD-1 immune checkpoint inhibitor or CTLA-4 blocker,TRIMs score is positively correlated with survival rate of patients,and can accurately predict the treatment effect(AUC>0.8).Identifying the TRIM genes with genetic and transcriptome alterations will directly contribute to cancer therapy in the context of predictive,preventive,and personalized medicine.Conclusions: In this paper,we systematically analyzed the genome and transcriptome across cancer types,and found that the TRIM family has a wide range of somatic mutations and transcriptome alterations in tumors,suggesting that the TRIM family plays an important role in tumor genesis and progression.This study further conducted a comprehensive review and analysis of the pharmacogenomics landscape about the TRIM family across cancer types,and established the TRIMs score system which can well predict the effects of tumor immunotherapy.It will provide clues for future development of therapeutic targets.In conclusion,the multi-omics analysis of the TRIM family will provide a comprehensive data resource and new insights into the clinical diagnosis and therapy of cancer.