Age-Specific Differences in Oncogenic Pathway Deregulation Seen in Human Breast Tumors 英文参考文献.docVIP

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Age-Specific Differences in Oncogenic Pathway Deregulation Seen in Human Breast Tumors 英文参考文献.doc

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Age-Specific Differences in Oncogenic Pathway Deregulation Seen in Human Breast Tumors 英文参考文献

Age-SpecificDifferencesinOncogenicPathway DeregulationSeeninHumanBreastTumors CareyK.Anders1,ChaitanyaR.Acharya2.,DavidS.Hsu1,2.,GloriaBroadwater3,KatherineGarman2,JohnA.Foekens4,YiZhang5,YixinWang5, KellyMarcom1,JeffreyR.Marks2,SayanMukherjee2,JosephR.Nevins2,KimberlyL.Blackwell1,AnilPotti1,2* 1DivisionofMedicalOncology,DepartmentofMedicine,DukeUniversity,Durham,NorthCarolina,UnitedStatesofAmerica,2InstituteforGenome SciencesandPolicy,DukeUniversity,Durham,NorthCarolina,UnitedStatesofAmerica,3CancerCenterBiostatistics,DukeUniversityMedicalCenter, Durham,NorthCarolina,UnitedStatesofAmerica,4ErasmusMedicalCenter,Rotterdam,TheNetherlands,5Veridex,Inc.,JohnsonandJohnson,San Diego,Californa,UnitedStatesofAmerica Purpose.Todefinethebiologydrivingtheaggressivenatureofbreastcancerarisinginyoungwomen.ExperimentalDesign. Among784patientswithearlystagebreastcancer,usingprospectively-defined,age-specificcohorts(young#45years;older $65years), 411 eligible patients (n=200#45years; n=211$65years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. Results. In comparing deregulation of oncogenic pathways between age groups,ahigherprobabilityofPI3K(p=0.006)andMyc(p=0.03)pathwayderegulationwasobservedinbreasttumorsarising inyoungerwomen.Whenevaluatinguniquepatternsofpathwayderegulation,alowprobabilityofSrcandE2Fderegulation intumorsofyoungerwomen,concurrentwithahigherprobabilityofPI3K,Myc,andb-catenin,conferredaworseprognosis (HR=4.15).Incontrast,ahigherprobabilityofSrcandE2Fpathwayactivationintumorsofolderwomen,withconcurrentlow probabilityofPI3K,Mycandb-cateninderegulation,wasassociatedwithpooreroutcome(HR=2.7).Inmultivariateanalyses, genomic clusters of pathway deregulation illustrate prognostic value. Conclusion. Results demonstrate that breast cancer arising in young women represents a distinct biologic entity char