1.Comprehensive Characterization Of Posttranscriptional Impairment-related 3’-UTR Mutations In 2,413 Whole Genomes Of Cancer Patients 2.Integrated Multi-omics Profiling Yields A Molecular Classification Scheme For Esophageal Squamous Cell Carcinoma

Purpose:The 3’untranslated region(3’-UTR)is the vital element regulating gene expression,which can drive or enhance cancer pathogenesis at the posttranscriptional gene regulation level by disrupting regulatory element binding and dysregulating oncogenic gene expression,but most studies have focused on variations in RNA-binding proteins(RBPs),miRNAs,alternative polyadenylation(APA)and RNA modifications.Somatic 3’-UTR mutations can also disrupt complex structure to dysregulate mRNA,contributing to tumorigenesis.Therefore,it is crucial to explore the effect of 3’-UTR mutations on pathological processes at the posttranscriptional level.Contents:We collected whole-genome data from 2,413 patients across 18 cancer types to identify 3’-UTR posttranscriptional impairment-related SNVs(3’-UTR piSNVs),which significantly enriched in tumor samples and were associated with worse patient survival,immune cell,checkpoint characteristics and canonical cancer pathways,and we further deciphered comprehensive characterization of 3’-UTR piSNVs in pan-cancer and predicted potential therapeutic drugs by CMAP workflow.Methods:We downloaded somatic mutations derived from WGS data of 2,413 patients across 18 cancer types in the PCAWG project and our in-house ESCC WGS samples,as well as corresponding clinical data,mRNA data and miRNA data;Then we used our updated algorithm "PIVar" to identify 3’-UTR piSNVs and enrich related RBPs;And we annotated RNA modifications and APA changes in 3’-UTR piSNVs with RMVar and APADB and identified possible binding miRNAs of 3’-UTR piSNVs with TargetScan,miRNASNP,starBase and miRDB software;In the meantime,we divided the cancer samples into two groups by 3’-UTR piSNV ratio to decipher the association with patient survival,tumor immune microenvironment and signaling pathways;Finally,we identified several potential therapeutic compounds for patients with specific cancer types by CMAP workflow.Results:To explore the posttranscriptional function of 3’-UTR somatic mutations in the genetic etiology of cancers,we collected whole-genome data from 2,413 patients across 18 cancer types(PCAWG project and our in-house ESCC data).Our updated algorithm,PIVar,revealed 25,216 3’-UTR posttranscriptional impairment-related SNVs(3’-UTR piSNVs)spanning 2,930 genes;24 related RBPs were significantly enriched.The somatic 3’-UTR piSNV ratio was markedly increased across all 18 cancer types,which was associated with worse survival for four cancer types.Several cancer-related genes,including PREX2,ADAMTS12,and PLXDC2,appeared to facilitate tumorigenesis at the protein and posttranscriptional regulation levels,whereas some 3’-UTR piSNV-affected genes,including RNF217,PGAM2,RBBP4,PIK3CA,CDYL2,EGFR and PIK3R2,functioned mainly via posttranscriptional mechanisms.Moreover,we assessed immune cell and checkpoint characteristics between the high/low 3’-UTR piSNV ratio groups and predicted 80 compounds associated with the 3’-UTR piSNV-affected gene expression signature.Conclusions:In summary,our study revealed the prevalence and clinical relevance of 3’-UTR piSNVs in cancers,and also demonstrates that in addition to affecting miRNAs,3’-UTR piSNVs perturb RBPs binding,APA and m6A RNA modification,which emphasized the importance of considering 3’-UTR piSNVs in cancer biology.Purpose:Esophageal squamous cell carcinoma(ESCC)is among the most common and lethal cancers.However,chemotherapy and radiotherapy remain the standard treatments with dismal survival rates as few therapeutic targets have been identified in ESCC.Integrated molecular analysis of human cancer has yielded molecular classification for precise management of cancer patients,and most studies were limited in single omic profiling in ESCC cohorts.Hence,it is essential and urgent to explore the integration of molecular changes across multi-omics in ESCC for benefiting clinical therapies.Contents:Our study is the first multi-omics study performed on a large cohort of ESCC,including whole genomic,epigenomic,transcriptomic and proteomic data.We deciphered comprehensive molecular characterization of all ESCC samples,and identified activation in different pathways and distinct dominant alterations,which could be used to personalize therapy for patients.Globally,we explored the correlation between gene expression levels and the methylation levels in the CGIs of promoter regions or gene body regions.Methods:We performed WGS,WGBS and RNA-seq in paired tumor and adjacent tissues from 155 ESCC patients,and we used MutSig,Oncodrivefm and dndscv tools to identify significant mutated genes(SMG).And we investigated the association of gene expression and methylation in promoter/gene body CGI regions.Results:Here,we comprehensively analyzed the whole genomic,epigenomic,transcriptomic and proteomic data of 155 esophageal squamous cell carcinomas(ESCC).We identified 17 significantly mutated genes,and found the five most frequently mutated genes:TP53,PIK3CA,NOTCH1,CDKN2A and ZNF750.Six typical signaling pathways were identified based on multiple omics data,including cell cycle,RTK-RAS-PI3K,cell differentiation,proliferation,NRF2,and chromatin remodeling pathways.Globally,we observed that the gene expression levels were negatively correlated with the methylation levels in the CGIs of promoter regions,but positively correlated with the methylation levels in the CGIs of gene body regionsConclusions:Collectively,these results emphasize the clinical value of molecular characteristics based on multi-omics data.The data from the comprehensive profiling of ESCC serves as a valuable resource to further improve the understanding and treatment of the disease.