Somatic Mutations of PIK3R1 Promote Gliomagenesis 英文参考文献.docVIP

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Somatic Mutations of PIK3R1 Promote Gliomagenesis 英文参考文献.doc

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Somatic Mutations of PIK3R1 Promote Gliomagenesis 英文参考文献

SomaticMutationsofPIK3R1PromoteGliomagenesis StevenN.Quayle1,JenniferY.Lee3,4,LydiaW.T.Cheung5,LiDing6,7,RuprechtWiedemeyer1, RobertW.Dewan1,EmmetHuang-Hobbs1,LiZhuang1,RichardK.Wilson6,7,KeithL.Ligon1,2 , GordonB.Mills5,LewisC.Cantley3,4,LyndaChin1*¤ 1DepartmentofMedicalOncology,Dana-FarberCancerInstitute,Boston,Massachusetts,UnitedStatesofAmerica,2CenterforMolecularOncologicPathology,Dana- FarberCancerInstitute,Boston,Massachusetts,UnitedStatesofAmerica,3DivisionofSignalTransduction,CancerCenter,BethIsraelDeaconessMedicalCenter,Boston, Massachusetts,UnitedStatesofAmerica,4DepartmentofSystemsBiology,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,5Departmentof SystemsBiology,TheUniversityofTexasM.D.AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica,6TheGenomeInstitute,WashingtonUniversitySchool ofMedicine,StLouis,Missouri,UnitedStatesofAmerica,7DepartmentofGenetics,WashingtonUniversitySchoolofMedicine,StLouis,Missouri,UnitedStatesofAmerica Abstract Thephosphoinositide3-kinase(PI3K)pathwayistargetedforfrequentalterationinglioblastoma(GBM)andisoneofthe core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 areobserved in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotestumorigenesisofprimarynormalhumanastrocytesinanorthotopicxenograftmodel.Furthermore,weshowthat cellsthataredependentonmutantP85a-mediatedPI3Ksignalingexhibitincreasedsensitivitytoasmallmoleculeinhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatmentwithinhibitorsofAKT. Citation:QuayleSN,LeeJY,CheungLWT,DingL,WiedemeyerR,etal.(2012)SomaticMutationsofPIK3R1Promot