Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy A Pharmacogenetic Study 英文参考文献.docVIP

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Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy A Pharmacogenetic Study 英文参考文献.doc

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Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy A Pharmacogenetic Study 英文参考文献

EffectofABCB1andABCC3Polymorphismson OsteosarcomaSurvivalafterChemotherapy:A PharmacogeneticStudy DanielaCaronia1,AnaPatin?o-Garcia2,AntonioPere′z-Mart?′nez3,GuillermoPita1,LeticiaTaisMoreno1, MartaZalacain-D?′ez2,BlancaMolina3,IsabelColmenero3,LuisSierrasesu′maga2,JavierBen?′tez1,4 ,Anna Gonzalez-Neira1* 1Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain, 2Department of Pediatrics, University of Navarra and University Clinic, Pamplona, Spain, 3Pediatric Oncology Department, Universitary Children’s Hospital Nin?o Jesus, Madrid, Spain, 4Human Genetics Group, Human Cancer Genetics Programme,SpanishNationalCancerResearchCentre,Madrid,Spain Abstract Background: Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whethercommongermlinepolymorphismsinchemotherapeutictransporterandmetabolicpathwaygenesofthedrugs usedinstandardosteosarcomatreatmentmaypredicttreatmentresponse. Methodology/Principal Findings: In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms(SNPs)and2CopyNumberVariants(CNVs)in24genesinvolvedinthemetabolismortransportofcisplatin, adriamycin, methotrexate, vincristine, andcyclophosphamide. We studied theassociation of thegenotypes with tumour responseandoverallsurvival.WefoundthatfourSNPsintwoATP-bindingcassettegenesweresignificantlyassociatedwith overallsurvival:rs4148416inABCC3(per-alleleHR=8.14,95%CI=2.73-20.2,p-value=5.161025),andthreeSNPsinABCB1, rs4148737 (per-allele HR=3.66, 95%CI=1.85–6.11, p-value=6.9610 ), rs1128503 and r(r2=1, per-allele HR=0.24, 95%CI=0.11–0.47 p-value=7.961025). Associations with these SNPs remained statistically significant after correctionformultipletesting(allcorrected