Multiple Pathway-Based Genetic Variations Associated with Tobacco Related Multiple Primary Neoplasms 英文参考文献.docVIP

MultiplePathway-BasedGeneticVariationsAssociated withTobaccoRelatedMultiplePrimaryNeoplasms AshwinKotnis1¤,JunghyunNamkung2,SadhanaKannan1,NallalaJayakrupakar1,TaesungPark3 ,Rajiv Sarin1*,RitaMulherkar1* 1Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India, 2Department of Epidemiology and Biostatistics, Case Western Reserve University,Cleveland,Ohio,UnitedStatesofAmerica,3DepartmentofStatistics,CollegeofNaturalScience,SeoulNationalUniversity,Seoul,Korea Abstract Background:Inordertoelucidateacombinationofgeneticalterationsthatdrivetobaccocarcinogenesiswehaveexplored auniquemodelsystemandanalyticalmethodforanunbiasedqualitativeandquantitativeassessmentofgene-geneand gene-environmentinteractions.Theobjectiveofthiscasecontrolstudywastoassessgeneticpredispositioninabiologically enrichedclinicalmodelsystemoftobaccorelatedcancers(TRC),occurringasMultiplePrimaryNeoplasms(MPN). Methods: Genotyping of 21 candidate Single Nucleotide Polymorphisms (SNP) from major metabolic pathways was performed in a cohort of 151 MPN cases and 210 cancer-free controls. Statistical analysis using logistic regression and MultifactorDimensionalityReduction(MDR)analysiswasperformedforstudyinghigherorderinteractionsamongvarious SNPsandtobaccohabit. Results:IncreasedriskassociationwasobservedforpatientswithatleastoneTRCintheupperaerodigestivetract(UADT) for variations in SULT1A1 Arg213His, mEH Tyr113His, hOGG1 Ser326Cys, XRCC1 Arg280His and BRCA2 Asn372His. Gene - environmentinteractionswereassessedusingMDRanalysis.TheoverallbestmodelbyMDRwastobaccohabit/p53(Arg/ Arg)/XRCC1(Arg399His)/mEH(Tyr113His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This modelalsoshowedsignificantassociationusinglogisticregressionanalysis. Conclusion: Thisis thefirst Indianstudy onamultipathway based approach tostudygenetic susceptibility tocancerin tobacco associated MPN. This approach could assist in planning additional studies for comprehensive under