Gemcitabine and Arabinosylcytosin Pharmacogenomics Genome-Wide Association and Drug Response Biomarkers 英文参考文献.docVIP

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Gemcitabine and Arabinosylcytosin Pharmacogenomics Genome-Wide Association and Drug Response Biomarkers 英文参考文献.doc

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Gemcitabine and Arabinosylcytosin Pharmacogenomics Genome-Wide Association and Drug Response Biomarkers 英文参考文献

GemcitabineandArabinosylcytosinPharmacogenomics: Genome-WideAssociationandDrugResponse Biomarkers LiangLi1,BrookeL.Fridley2,KrishnaKalari2,GregoryJenkins2,AnthonyBatzler2,RichardM. Weinshilboum1,LieweiWang1* 1Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America, 2Health Sciences Research, Mayo Clinic, Rochester,Minnesota,UnitedStatesofAmerica Abstract Cancer patients show large individual variation in their response to chemotherapeutic agents. Gemcitabine (dFdC) and AraC,twocytidineanalogues,haveshownsignificantactivityagainstavarietyoftumors.Wepreviouslyusedexpression data from a lymphoblastoid cell line-based model system to identify genes that might be important for the two drug cytotoxicity.Inthepresentstudy,weusedthatsamemodelsystemtoperformagenome-wideassociation(GWA)studyto testthehypothesisthatcommongeneticvariationmightinfluencebothgeneexpressionandresponsetothetwodrugs. Specifically, genome-wide single nucleotide polymorphisms (SNPs) and mRNA expression data were obtained using the Illumina 550KH HumanHap550 SNP Chip and Affymetrix U133 Plus 2.0 GeneChip, respectively, for 174 ethnically-defined ‘‘HumanVariationPanel’’lymphoblastoidcelllines.GemcitabineandAraCcytotoxicityassayswereperformedtoobtainIC50 values for the cell lines. We then performed GWA studies with SNPs, gene expression and IC50 of these two drugs. This approachidentifiedSNPsthatwereassociatedwithgemcitabineorAraCIC50valuesandwiththeexpressionregulationfor 29genesor30genes,respectively.OneSNPinIQGAP2(rs3797418)wassignificantlyassociatedwithvariationinboththe expression of multiple genes and gemcitabine and AraC IC50. A second SNP in TGM3 (rs6082527) was also significantly associatedwithmultiplegeneexpressionandgemcitabineIC50.Toconfirmtheassociationresults,weperformedsiRNA knockdownofselectedgeneswithexpressionthatwasassociatedwithrs3797418andrs6082527intumorcellandthe knockdownalteredgemcitabineorAraCsensitivity,confirmingourass