Mutational Signatures of De-Differentiation in Functional Non-Coding Regions of Melanoma Genomes 英文参考文献.docVIP

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Mutational Signatures of De-Differentiation in Functional Non-Coding Regions of Melanoma Genomes 英文参考文献.doc

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Mutational Signatures of De-Differentiation in Functional Non-Coding Regions of Melanoma Genomes 英文参考文献

MutationalSignaturesofDe-Differentiationin FunctionalNon-CodingRegionsofMelanomaGenomes StephenC.J.Parker1,JaredGartner1,IsabelCardenas-Navia1,XiaomuWei1,HaticeOzelAbaan1, SubramanianS.Ajay1¤,NancyF.Hansen1,LingyunSong2,UmeshK.Bhanot3,J.KeithKillian4, YevgeniyGindin4,5,RobertL.Walker4,PaulS.Meltzer4,JamesC.Mullikin1,TerrenceS.Furey6, GregoryE.Crawford2,StevenA.Rosenberg4,YardenaSamuels1*,ElliottH.Margulies1¤* 1NationalHumanGenomeResearchInstitute,NationalInstitutesofHealth,Bethesda,Maryland,UnitedStatesofAmerica,2InstituteforGenomeSciencesandPolicy, DukeUniversity,Durham,NorthCarolina,UnitedStatesofAmerica,3DepartmentofPathology,MemorialSloan-KetteringCancerCenter,NewYork,NewYork,United StatesofAmerica,4NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,UnitedStatesofAmerica,5GraduatePrograminBioinformatics,Boston University,Boston,Massachusetts,UnitedStatesofAmerica,6DepartmentofGenetics,DepartmentofBiology,LinebergerComprehensiveCancerCenter,andCarolina CenterforGenomeSciences,TheUniversityofNorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica Abstract Much emphasis has been placed on the identification, functional characterization, and therapeutic potential of somatic variantsintumorgenomes.However,themajorityofsomaticvariantslieoutsidecodingregionsandtheirroleincancer progression remains to be determined. In order to establish a system to test the functional importance of non-coding somaticvariantsincancer,wecreatedalow-passagecellcultureofametastaticmelanomatumorsample.Asafoundation forinterpretingfunctionalassays,weperformedwhole-genomesequencingandanalysisofthiscellculture,themetastatic tumorfromwhichitwasderived,andthepatient-matchednormalgenomes.Whencomparingsomaticmutationsidentified inthecellcultureandtissuegenomes,weobserveconcordanceatthemajorityofsinglenucleotidevariants,whereascopy numberchanges aremorevariable. Tounderstand the functionalimpact ofnon-coding somaticvariation,weleveraged functional data generate