| Background and Objective:Esophageal squamous cell carcinoma?ESCC?ranks the fourth leading cause of cancer death and approximately half of the world's 500,000 new ESCC cases each year occur in China.The mechanism of its occurrence and development is not clear.There are currently no specific molecule-targeting agents for ESCC treatment and therefore the long-term outcome of this cancer is still dismal.Since life is a complex regulatory system in which the regulation of gene mutations,epigenetic alterations,abnormal gene expression as well as anomalous variations in signal pathway are related with the occurrence and development of diseases,it is obvious that finding therapeutic factors using single omic data analysis has its limitation.Therefore,we explored the molecular mechanism of development of ESCC through integrative analysis of multi-omics data from different levels and resources in this study,which would provide innovation perspectives and new theoretical basis for early diagnosis,personalized treatment and medicine guide of ESCC.Methods:In this study,we performed whole genome sequencing and transcriptome sequencing of 94 individuals with ESCC.We analyzed the whole genome genetic variation spectrum,somatic mutation spectrum and transcriptome expression profile to establish the abnormal molecular regulation network of ESCC.In addition,7,875,353 SNPs in 1,088 ESCC patients with follow-up information for more than 5 years were analysed using genome wide association method,and then the related SNPs were validated in 1,479 independent samples of ESCC to explore the SNPs and genes associated with overall survival time of ESCC.Results:First,we identified six mutational signatures?E1-E6?,and E4 was unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes.Second,we confirmed significantly recurrent mutations in 20 protein-coding genes,4 long non-coding RNAs,1 promoter and 10 untranslational regions.Thirdly,we identified 23 focal regions with recurrent gain of copy number and 34 regions with recurrent loss of copy number,in which 14 genes had aberrant mRNA expression in ESCC,HNSCC and LUSCC.In addition,we first identified LRP1B and TTC28 were the most frequently affected genes by structual variation in ESCC.The aberrant cell cycle and PI3K/AKT pathways seemed critical in ESCC.Moreover,we found that the rs4919698 T>G genetic variation in the intron of EIF4B increased the death risk of ESCC by genome wide association study(HR=1.67;95%CI=1.32-2.12;P=2.01×10-6).Conclusions:We reported an integrative analysis of genomic signatures,SNVs,CNVs,SVs and their correlations with mRNA expression in ESCC from Chinese individuals.We have comprehensively characterized the genomic landscape features in ESCC.Through an extended genome wide association study,we found that rs4919698 was significantly associated with overall survival of ESCC patients.These results may provide clues to environmental etiologic factors and guide to develop precision treatment and prevention of ESCC. |
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