Study On The Pathogenesis Of Sacral Chordoma Based On Whole-Exome Squencing

Objective:To explore the role of related genes in the tumorigenesis,development,metastasis and recurrence of chordoma and potential therapeutic targets.we used whole-exome sequencing and biological information analysis to investigate mutation genes in sacral chordoma.Methods:We sequenced the exome of eight tumor samples and eight preoperative peripheral blood samples from sacral chordoma patients who were treated at the First Affiliated Hospital of Soochow University from November 2014 to November 2018.Then,we analyzed the sequencing data from mutation spectrum,mutation signature,known driver gene,pathway enrichment analysis,and Significantly mutated genes After quality control of sequencing data,comparison of reference genomes,analysis of mutation and identification of somatic mutation.Results:1.Satisfied sequencing data were obtained after the analysis of raw sequencing data.The average coverage depth of tumor and blood samples were 136 × and 139 X.The sequencing coverage of tumor and blood samples whose coverage depth were above 10 X were above 99%.2.We totally identified 13059 somatic SNVs and 865 InDels after filtering out normal germline mutations.3.We next characterized the mutation spectrum and mutation signature.The highest frequency of C>T transitions in somatic mutation was identified,the second highest frequency is T>C transitions.We identified three mutation signatures within chordoma genomes by the non-negative matrix factorization method and the signature B predominated among 75%samples which was most similar to the signature 1 displayed on the COSMIC.4.We screened out 21 known driver genes after comparing somatic mutation to three known driver gene databases.5.We screened out 20 signal pathways with p-values<0.05 and the smallest.6.Three significantly mutated genes were identified by using MuSiC software.Conclusions:1.The endogenous mutational process initiated by the spontaneous deamination of 5-methylcytosine may be a driver event of sacral chordoma.2.The PI3K/AKT/mTOR signal pathway plays an important role in the development of sacral chordoma and the known driver genes PIK3CA,PIK3R1 and PTEN may be potential therapeutic targets of chordoma.3.The significantly mutated gene CLDN9 may be a key gene in the development of sacral chordoma and change the aggressiveness of chordoma by CAMs.