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©2014NatureAmerica,Inc.Allrightsreserved.NatureGeNetics ADVANCEONLINEPUBLICATIONlettersIndividuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of CT mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR) 0.05) of non-silent mutations include TP53 (47.%), KRAS (7.8%) and ERBB3 (.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (2/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P = 0.00). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.GBCisarareneoplasmwithanincidenceof2.5in100,000indi-viduals1,2.Riskfactorsforitsdevelopmentincludethepresenceofgallstones,chronicinflammationandthepresenceofanomalouspancreatobiliaryductaljunctions3.IndividualswithGBCoftendonotshowearlysymptomsandmayreceivelatediagnosesandunsat-isfactorytreatments,leadingtopoorprognosis.ThemediansurvivaltimeforindividualswithGBCislessthan1year4.GBCcellsaregen-erallyhighlymetastatic,butlittleisknownabouttheirpathogenesis.Whole-exomeandtargetedgenesequencingofgallbladdercarcinomaidentifiesrecurrentmutationsintheErbBpathwayMaolanLi1,2,13,ZhouZhang1–3,13,XiaoguangLi4,13,JunyiYe5,XiangsongWu1,2,ZhujunTan1,2,ChangLiu6,BaiyongShen7,Xu-AnWang1,2,WenguangWu1,2,DaizhanZhou3,DiZhang3,TingWang3,BingyaLiu7,KaiQu6,QichenDing1,2,HaoWeng1,2,QianDing1,2,JiashengMu1,2,YijunShu1,2,RunfaBao1,2,YangCao1,2,PeizhanChen4,TianyuLiu1,2,LinJiang1,2,YunpingHu1,2,PingDong1,2,JunGu1,2,WeiLu1,2,WeibinShi1,2,JianhuaLu1,2,WeiGong1,2,ZhaohuiTang1,2,YongZhang1,2,XuefengWang1,2,YEugeneChin8,XiaolingWeng5,HongZhang5,WeiTang9,YonglanZheng10,LinHe3,5,11,HuiWang4,12,14,YunLiu5,14&YingbinLiu1,2,141DepartmentofGeneralSurgery,XinhuaHospitalaffiliatedtoShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,China.2InstituteofBiliaryTractDisease,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,China.3KeyLaboratoryfortheGeneticsofDevelopmentalandNeuropsychiatricDisorders(MinistryofEducation),Bio-XCenter,ShanghaiJiaoTongUniversity,Shanghai,China.4KeyLaboratoryofFoodSafetyResearch,InstituteforNutritionalSciences,ShanghaiInstitutesforBiologicalSciences,ChineseAcademyofSciences,UniversityofChineseAcademyofSciences,Shanghai,China.5InstitutesofBiomedicalSciences,FudanUniversity,Shanghai,China.6DepartmentofHepatobiliarySurgery,TheFirstAffiliatedHospitalofMedicalCollege,Xi′anJiaotongUniversity,Xi’an,China.7DepartmentofGeneralSurgery,RuijinHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,China.8InstituteofHealthSciences,ShanghaiInstitutesforBiologicalSciences,ChineseAcademyofSciences,Shanghai,China.9LaboratoryofHumanCarcinogenesis,CenterforCancerResearch,NationalCancerInstitute,USNationalInstitutesofHealth,Bethesda,Maryland,USA.10DepartmentofMedicine,TheUniversityofChicago,Chicago,Illinois,USA.11Women’sHospital,ZhejiangUniversitySchoolofMedicine,Hangzhou,China.12KeyLaboratoryofFoodSafetyRiskAssessment,MinistryofHealth,Beijing,China.13Theseauthorscontributedequallytothiswork.14Theseauthorsjointlydirectedthiswork.CorrespondenceshouldbeaddressedtoYingbinLiu(liuybphd@126.com),YunLiu(superliuyun@fudan.edu.cn)orH.Wang(huiwang@sibs.ac.cn).Received23March;accepted11June;publishedonline6July2014;doi:10.1038/ng.3030ACAGATCACGCT0.200.150.100.05MutationsperMb0A_AA_CA_GA_TC_AC_CC_GC_TG_AG_CG_GG_TT_AT_CT_GT_TFigure1SomaticSNVsignatureinGBC.The4,592somaticSNVs(including1,450non-silentand3,142silentSNVs)foundin32GBCexomesweredividedinto96subgroupsdefinedbysubstitutionclassandadjacentbases.Eachcolumnaroundthecirclerepresentsasubgroup,andtheheightofeachcolumnshowsmutationfrequencyperMb.©2014NatureAmerica,Inc.Allrightsreserved.2 ADVANCEONLINEPUBLICATIONNatureGeNeticslettersThusfar,moststudieshavefocusedonalimitednumberofcandidategenes2,5.ArecentstudyanalyzedexomesequencefromnineGBCtumorsandidentifiedTP53asasignificantlymutatedgene6.KnowledgeofthespectrumofsomaticmutationsinGBCremainsincomplete.ToprofilethesomaticmutationspectruminGBCs,weperformedwhole-exomesequencingon32pairsofclinicallyandpathologi-callycharacterizedGBCtissuesandcase-matchednormaltissues(SupplementaryFig.1andSupplementaryTables1–3).Usingstrin-gentcriteria,weidentified1,450somaticsingle-nucleotidevariations(SNVs)and34somaticinsertionsordeletions(indels)thatwerepre-dictedtoalterprotein-codingsequence(definedbyhighormoderateimpactinSnpEff7;SupplementaryTable4).Theoverallmutationratewas1.42mutationsperMb(SupplementaryTable5).Thenucleotidemutationpatterncanbeindicativeofspecificmuta-genesismechanismsoccurringintumorcells8–10
本文标题:Whole-exome-and-targeted-gene-sequencing-of-gallbl
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