IndianJHumGenet.2011SepDec17(3):132144.

PMCID:PMC3276980

doi:10.4103/09716866.92087

Acomprehensivereviewonhostgeneticsusceptibilitytohumanpapillomavirusinfectionand
progressiontocervicalcancer
KoushikChattopadhyay
NelsonR.MandelaSchoolofMedicine,UniversityofKwaZuluNatal,Durban,RepublicofSouthAfrica
Addressforcorrespondence:Dr.KoushikChattopadhyay,Flatno.12,Roseric,67LenaArhensRoad,Bulwer,Durban4001,RepublicofSouthAfrica.Email:
chattopadhyayk@india.com
Copyright:IndianJournalofHumanGenetics
ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,whichpermitsunrestricteduse,distribution,
andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract
Cervicalcanceristhesecondmostcommoncancerinwomenworldwide.Thisiscausedbyoncogenictypesofhumanpapillomavirus
(HPV)infection.AlthoughlargenumbersofyoungsexuallyactivewomengetHPVinfected,onlyasmallfractiondevelopcervical
cancer.ThispointstodifferentcofactorsforregressionofHPVinfectionorprogressiontocervicalcancer.Hostgeneticfactorsplayan
importantroleintheoutcomeofsuchcomplexormultifactordiseasessuchascervicalcancerandarealsoknowntoregulatetherateof
diseaseprogression.Theaimofthisreviewistocompiletheadvancesinthefieldofhostgeneticsofcervicalcancer.MEDLINE
databasewassearchedusingtheterms,HPV,cervical,CIN,polymorphism(s),cervical+*thenameofthegene*andHPV+
*thenameofthegene*.ThisreviewfocusesonthemajorhostgenesreportedtoaffecttheprogressiontocervicalcancerinHPV
infectedindividuals.
Keywords:Cervicalcancer,genetics,HPV,polymorphism,progression
Introduction

Cervicalcanceristhesecondmostcommoncancerinwomenworldwidewithanannual493,243casesand273,505deaths.[1]The
incidenceofcervicalcancerishigherindevelopingcountriesandlessindevelopedcountrieswithaneffectivecervicalscreening
program.About80%ofthecasesoccurindevelopingcountries.Insomeoftheplaces,cervicalcanceristhemostcommoncancerin
women.LatinAmerica,theCaribbean,subSaharanAfricaandSouthandSouthEastAsiahavethehighestincidencerate.[2,3]The
maincauseofcervicalcancerisinfectionbyhumanpapillomavirus(HPV).
DuringtheirlifetimemanywomenbecomeinfectedwithHPV,butinterestinglyonlyasmallfractionofthemdevelopcervicalcancer
andtherestregresstoanormalhealthystate.Thissuggeststheroleofadditionalriskfactorsplayinganimportantroleintheoutcomeof
theinfection.Theseriskfactorsincludehostandviralgeneticfactorsalongwithenvironmentalandlifestylefactors.
HostgeneticriskfactorstoHPVinfectionandcervicalcancer:Thegeneticlinktocervicalcancerdevelopmentisstronglysupported
byepidemiologicalstudies.Ahereditarycomponentofcervicaltumorswasdetectedincomparisonsoftwins[4]andinamotherdaughter
familystudy.Thepossibilityofhostgeneticpredispositionisstrengthenedbytheobservationthatbiologicalfirstdegreerelativesofthe
womenwhohavedevelopedacervicaltumorexperienceatwofoldriskofdevelopingcervicaltumorcomparedtononbiological
relativesofwomenwithcervicaltumor.[5]Theheritabilityofcervicaltumorshasbeendeterminedas27%.[6]
MaterialsandMethods
AreviewofpeerreviewedliteratureintheMEDLINEdatabasewasconducted.Majorhostgenesthathavebeenconsideredtoplay
eitherasusceptibleorprotectiveroleinthedevelopmentofcervicalintraepithelialneoplasia(CIN)orcervicalcancerfromHPVinfection
havebeendiscussed.Thefollowingmedicalsubjectheadings(MESH)andtextwordswereusedtosearchtheMEDLINEdatabase,
HPV,cervical,CIN,andpolymorphism(s).Separatesearcheswerecarriedoutforeachindividualcandidatehostgeneusingthe
searchterms,cervical,*thenameofthegene*,HPV,*thenameofthegene*.Studiesonhumansubjectsandpublishedinany
languageswereconsidered.Thestudiesthatcomparedalleleorgenotypefrequenciesofcandidatehostgenesincervicalcancerpatients
orpatientsinanygradeofCINwithnoncanceroushealthyindividualsoramongthedifferentgroupsofcaseswereeligibleforthis
review.[7,8]
Humanleukocyteantigengenes(HLA):HLAcomprisesafamilyofgeneswithinthemajorhistocompatibilitycomplex(MHC)
localizedonChromosome6(6p).HLAgenesaredividedinto2majorclassesClassIgenes(mostnotablyHLAA,BandCgenes)and
ClassIIgenes(mostnotablyDR,DQandDPgenes).HLAClassImolecules(HLAClassIgeneproduct)areexpressedinallnucleated
cellsandpresentforeignantigenstoCD8+CytotoxicTlymphocytes(CTLs)(acquiredimmuneresponse).CD8+Tcellshavetheability
tokilltheforeignantigenpresentedtothembytheHLAClassImolecules.HLAClassIImolecules(HLAClassIIgeneproducts)are

typicallyexpressedincellsoftheimmunesystem,suchasdendriticcells,macrophages,Blymphocytesandareknowntobeimportantin
presentingantigenicpeptidestoCD4+helperTlymphocytes.ClassIandClassIIHLAgenesarehighlypolymorphic,anecessityfor
evolutionarysurvivalasitprovidesresistancetopotentialpathogensbybindingandpresentingawidevarietyofantigenicpeptides.
PresenceofHLAmoleculesthatbindHPVantigenswithhighaffinitymightconferaprotectiveeffectontheprogressionofcervical
cancerontheotherhandpresenceofHLAmoleculesthatdonotrecognizeandbindawidevarietyofHPVantigensmightbeassociated
withthesusceptibilityofthedisease.
HLAA,BandCgeneshavebeeninvestigatedbyseveralgroupsindifferentpopulationinrelationtocervicalcancer.Contrastingresults
havebeenfound.HLAA2,A*01,A*24,A*1104,B7,B15,B63andCw*0202locihavebeenreportedtobeassociatedwithincreased
riskofdevelopingcervicalcancer.[919]Ontheotherhand,aprotectiveeffecthasbeenfoundforHLAA*0207/0215NorA*2402.[18]
HLADQandDRgeneshavebeenextensivelystudiedbymanygroupsindifferentpopulationacrosstheglobe.DQA1*01,*03,
DQB1*02,*03,*04,*06andDQw1,DQw3alleleshavebeenassociatedwithincreasedriskofdevelopingthedisease.
[10,11,14,2047]AprotectiveassociationhasalsobeenfoundwithDQA1*0501andDQB1*0201,*0103,*0301/*0501,*04,*05,
*050201,*06alleles.[27,33,34,44,45,4851]DRB1*4,*5,*11,*13,*15,*16werefoundtobesusceptibleloci.
[12,14,15,30,31,36,3840,42,43,5157]andDR*1,*2,*4,*6,*12,*13,*14,*15werefoundtobeprotectiveloci.
[1012,15,43,48,51,58]OnlyafewstudiesinvestigatedtheDOandDPgenesandreportedapositiveassociationwithseverityofthe
diseasewithboththeDOB1*03andDPB1genes.[40,59,60]
TheinteractionsofDQDRhaplotypesandtheireffectoncervicalcancershowedinterestingresults.Anincreasedassociationwiththe
diseasewasfoundforDRB1DQB1(0403,1506,1605,0804)andDQA1DQB1(0106,0503).[3032,40,54,6165]Aprotective
effectwasalsofoundforDQA1DQB1(0202),DRB1DRB1(130102)andDRB1DQB1(1506).[10,25,46,52,60,61,65]
Tp53:Tp53genelocalizedonchromosome17q13.1encodesprotein53(p53)andisatumorsuppressorgenethatregulatesthecell
cycle.IncaseofDNAdamage,Tp53isupregulatedandcausesG1arrestofthecellallowingthegeneticdamagetoberepaired.HPV
16and18encodestwomajoroncoproteins,E6andE7.Thesetwoproteinsinterferewiththecellulartumorsuppressorproteins.Tp53
geneiscommonlyknowntohaveapolymorphismincodon72withtwoallelesencodingeitherarginine(Arg/Arg)orpraline(pro/pro).
ThispolymorphismwasfirstinvestigatedbyStoreyet.al.incervicalcancerpatients.Theyreportedaseventimeshigherriskof
developingHPVassociatedcervicalcarcinogenesisinindividualswithArghomozygositythanwithheterozygousgenotype.Several
groupsinvestigatedtheTp53codon72polymorphismincervicalcancersusceptibilityindifferentethnicgroupswithcontradictory
results.ManystudiesonvariousethnicgroupsfoundTp53codon72ArgasariskalleleforHPVinfectionandprogressiontocervical
cancercomparingcasecontrolindividuals.[6684]Tp53codon72Argwasfoundtobeassociatedwithadenocarcinomabutnotwith

squamouscellcarcinoma(SCC)andconferringsusceptibleeffecttoGSTT1nullindividuals.Alargenumberofcasecontrolstudiesin
differentethnicgroupsfailedtoshowanassociationofArgallelewithHPVinfectionandprogressiontocervicalcancer.[78,85117]
Tp53codon72ArgallelewasalsofoundtohavedecreasedassociationtocervicalabnormalitiesandHPVinfection.Ontheotherhand,
theTp53Pro/Progenotypewasreportedtohaveahigherriskindevelopingcervicalcancer.
Tumornecrosisfactor(TNF)genes:TNFgenesaresituatedcentromerictotheHLABgenesandtelomerictotheC2genes.[47]TNFis
acytokineandisproducedmainlybyactivatedmacrophages.TNFgenesproducetwoimmunologicallyimportantproteins,TNFand
TNF.Theseproteinsplayacrucialroleintheinflammatoryresponseandimmuneactivitiestowardtumorcells.[118]TNFactsthrough
theTNFReceptors(TNFR1andR2)andisapartofthecomplexpathwayoftriggeringapoptosis.ThebindingofTNFtoTNFR1
initiatesthepathwaythatleadstocaspaseactivationviatheadapterproteins(TRADD,FADD)committingthecelltoapoptosis.This
bindingisalsoinvolvedinactivationoftranscriptionfactorsinvolvedincellsurvivalandinflammatoryresponses.[119]TNFalso
interactswithtumorcellstotriggercytolysis.CancerpatientshavebeenfoundwithincreasedlevelsofTNF.[120,121]Several
polymorphicsiteshavebeenreportedinTNFlocusincludingfivemicrosatellitesofTNFae.[122]TNFaiscloselylinkedtoTNFgene
andcontains14differentalleles(a1a14)withanAC/GTdinucelotiderepeat.Severalgroupsinvestigatedtheroleofvarious
polymorphicsitesofTNFgeneinassociationtocervicalcancerindifferentethnicpopulations.Apositiveassociationwasfoundwith
cervicalcancerandthepresenceofTNFa8,TNF572,857,863andalsowithTNFG308A.[123125]G308Adidnotshowany
associationinSouthAfricanpopulation.[126]
MHCclassIpolypeptiderelatedsequenceA(MICA):TheMICAgeneislocatedonchromosome6,centromerictoHLABand
telomerictoTNFandencodesthehighlypolymorphicMHC(HLA)classIchainrelatedgeneA.TheMICAisexpressedby
keratinocytesandepithelialcellsonthecellsurfaceandinteractswithTcellsandhasanimportantroleinimmuneresponseanddirect
inductionofmucosalimmunity.[125,127]Theproteinfunctionsasastressinducedantigenbroadlyrecognizedbyintestinalepithelial
gammadeltaTcells.MICAisalsoinvolvedinpresentationofforeignantigenstotheimmunesystem.[128]Exon5ofMICAgene
containsamicrosatellitelocuswith5alleles,instronglinkagedisequilibriumwithHLABalleles.[129]Differentpolymorphicsitesof
MICAwereinvestigatedinSwedishandAsianpopulationbutnonewerefoundtohaveanassociationwithcervicalcancer.
WAF1/p21:TheWAF1/p21geneislocatedonchromosome6p21.2andisaTp53mediator.Anychangesinthisgenemayaffectthe
regulationofcellgrowthandresultinexcessiveproliferationofcancercells.Aserinetoargininechangehasbeenwelldocumented
followedbyaCtoAtransversionatthethirdbaseofcodon31.[130,131]Differentgroupsstudiedthispolymorphismwithmixedresults.
Ser/SergenotypewasfoundtobethesusceptiblegenotypeforadenocarcinomainhighriskHPVbutnotforSCC.[72]Ser/Arggenotype
wasassociatedwithsusceptibilitytocervicalcancer.[132]Somestudiesfailedtofindanyassociationbetweenthispolymorphismand

cervicalcancer.[133,134]
Interleukin10(IL10):IL10geneislocalizedonchromosome1.IL10isaTH2typecytokineproducesasuppressiveeffectoncell
mediatedimmunity(CMI).[135137]IncreasedexpressionofIL10isreportedinSCC[138]andincreasedserumlevelsofIL10in
cervicalcancer.[139]Oneofthepolymorphismsthatisassociatedwithlow,mediumorhighproductionofIL10situatesinthepromoter
regionofthegeneatposition1082.[140]Severalstudiesinvestigatedthispolymorphismwithconflictingresults.1082A/Gwasfound
tobetheriskgenotypeforcervicalcancer.[141]However,1082GallelewasshowntohaveaninverseassociationwithHPV
persistency.[142]Afewstudiesfailedtofindanyassociationofthispolymorphismwithcervicalcancer.[143146]
Methylenetetrahydrofolatereductase(MTHFR):MTHFRgeneissituatedonchromosome1p36.3.[147]MTHFRenzymeregulatesthe
metabolismoffolateandmethionine,whicharecriticalforDNAmethylationandsynthesis.CtoTtransitionatnucleotideposition677
oftheMTHFRgeneresultsinalaninetovaline.Comparedtohomozygouswildtype(Ala/Ala)bothheterozygous(Ala/Val)and
homozygous(Val/Val)variantsreduceMTHFRenzymeactivityinindividualswithalowfolatestatus.[148,149]Hencethis
polymorphismmightcauseanabnormalDNAmethylationandDNAsynthesiswhichcanleadtoanincreasedriskofdevelopingcancer.
ThispolymorphismislessfrequentinblacksthaninCaucasians.[150]Differentgroupsinvestigatedtheeffectofthispolymorphismin
differentcasecontrolpopulationswithconflictingresults.Somefoundthepolymorphismasariskfactortodevelopcervical
cancer[151154]whileothersdidnot.[155157]AreducedriskofdevelopingCINII/IIIforthemutanttypecarrierscomparedtothe
wildtypecarriersofthispolymorphismwasalsoreported.[152]
Interferongamma(IFN):IFNgeneismappedonchromosome6.IFNiscrucialindefendingagainstvirusesandintheinduction
ofimmunemediatedinflammatoryresponses.[158]TtoAchangeatthe+874positionfromtranslationstartsiteinthefirstintronofIFN
genewasreportedtohaveahighIFNproduction.Alow(A/A),medium(A/T)andhigh(T/T)IFNproductionisassociatedwith
+874singlenucleotidepolymorphism(SNP).[159]Thispolymorphismdidnotshowanyassociationwithcancerofthecervix.[146]
Chemokinereceptor2(CCR2):CCR2geneissituatedonchromosome3p21.Oneoftheearliestresponsesofhumanbodytoinjuryor
infectionisthereleaseofchemokinesthattriggerspenetrationoflocalinflammatoryandimmunecells.[160]Ithasbeenpostulatedthat
HPVdisruptstheinteractionbetweenepithelialcellsandtheimmunesystembyderegulatingtheexpressionofchemokineswhichhave
beenassociatedwithbacterialorviralinfections,autoimmunediseases,heartdiseasesandmanyothers.[161]MCP1isaligandfor
chemokinereceptorCCR2producedlargelybytumorcells.MCP1isresponsibleforrecruitingmacrophagestotumorsinbladder,
cervix,ovary,lungandbreast.Thoughmacrophagesdisplaytumorcytotoxicity,tumorassociatedmacrophages(TAMs)mainlyhave
protumorfunctions[162]andhelpintumorangiogenesis.MoreexpressionofMCP1recruitsmoremacrophagesandspeedsupthe
processoftumorprogression.WhentheepithelialcellsareinfectedbyHPV,itreducestheMCP1expressionfromlowgradesquamous

intraepitheliallesions(LSIL)tohighgradesquamousintraepitheliallesions(HSIL)[163]andthelevelsofMCP1expressionincreases
againfromHSILtoinvasivecervicalcancer(ICC).TumorcellshavebeenreportedwithhighlevelsofMCP1expression.[164]
Macrophages,whicharerecruitedbyMCP1chemokine,expressCCR2ontheircellsurface.
CCR2hastwoisoformsCCR2AandCCR2BoriginatedfromtheCCR2genebyalternativesplicing.Asinglenucleotide
polymorphism(SNP)ofGtoAatposition190ofCCR2genechangesaminoacidvaline(GTC)toisoleucine(ATC)atcodon64
(CCR2V64I).ThisconservativeaminoacidchangetakesplaceinthefirsttransmembranedomainofCCR2AandCCR2B.Thischange
makesCCR2AmorestableandincreasesitshalflifebutdoesnotanywayaffectthestabilityofCCR2Bisoform.Theincreasedstability
ofCCR2AmightaccumulatealargeamountofthisisoformonthemacrophagecellsurfacewhichalsointerfereswiththeCCR2B
function.Thismisleadsthecellsandthemacrophagerecruitmentdropsduringthedevelopmentofthetumorwhichhampersthetumor
angiogenesisandeventuallygivesaprotectiveeffecttothetumorprogression.Thispolymorphism(CCR2V64I)hasbeenextensively
studiedandseveralreportsshowaprotectiveroleofthepolymorphismwithAIDS,[165168]multiplesclerosis[169]andbreastcancer.
[170]ThispolymorphismwasstudiedinPortuguese,SwedishandSouthAfricanblackandmixedancestrypopulation.Comparing
squamousintraepitheliallesions(SIL)withICCshowedaprotectiveeffectoftheAallelefordevelopingICCfromSIL.[171]TheA
allelewasalsofoundtobeariskallelefordevelopingHSIL[172]andcervicalcancer[173]comparedtohealthycontrols.Contrastingto
that,adecreasedriskofdevelopingcervicalcancerwasreportedinthepresenceoftheAallele.[174]Somegroupsfailedtofindan
associationofthispolymorphismwithcervicalcancer,[175]precancerouslesionsorHPVinfection.[173]
FasandFasligand(FasL):Fasgeneissituatedonchromosome10q24.1.Theroleofcorruptedapoptosishaslongbeenwell
documentedfordevelopmentoftumorigenesis.Tumorigenesisisachievednotonlybyincreasedcellproliferationbutalsobyadecreased
apoptoticrate.[176]Defectsinthemechanismofapoptosisgeneshavebeenidentifiedascancercausingagents.Apoptosisisdependent
greatlybysignalsfromcellsurfacedeathreceptorFas/CD95.TogetherwithFasligand(FasL),ittriggersprogrammedcelldeath.[177]
ThesignalproducedbytheDNAbindingoftranscriptionfactorsSP1(stimulatoryprotein1)andSTAT1(signaltransducerandactivator
oftranscription1)areassociatedwithtranscriptionalactivationandexpressionofFasgene.Fas1377bpand670bparesituatedwithin
SP1andSTAT1bindingsitesrespectively.IthasbeenshownthatachangeofAat1377ofFaspromoterconsiderablyreducesSP1
bindingcomparedto1377GresultinginadecreaseofFasgeneexpression.[178,179]Gammainterferonactivationsignal(GAS)isa
bindingelementresponsibleforDNAbindingofSTAT1.670bpislocatedwithinGASbindingsite.AchangeofGat670ofFas
promoterregionpartiallyorcompletelyabolishestheGASelement,hencesignificantlyreducestheFasgeneexpression[180,181]which
resultsindecreasedactivationinducedcelldeath(AICD)anduncontrolledgrowthofthevirus.Ithasalsobeenshownthatahigherbasal
expressionofFasLisassociatedwiththeCalleleatposition844ofFasLgenethanwiththeTallele.[181]ReducedexpressionofFasL
inhibitstheapoptoticactivityoftheFasFasLpathway.StudiesonthesepolymorphismswithcervicalcancerrangingfromAsian,

EuropeantoBlackandmixedancestryAfricanhaveshownconflictingresults.AnassociationofFas670AalleleandA/Agenotype
withhigherriskofdevelopingcervicalcancerwasreported.[182]Otherstudiesoncasecontrolsandaffectedsibpairs(ASP)didnotfind
anyassociationofthispolymorphismwithcancerofthecervix.[183185]Fas1377polymorphismwasnotfoundtobeassociatedwith
diseaseseverity.[185,186]FasL844CalleleandC/Cgenotypewasfoundtobesusceptibletocervicalcancer[187]however,other
groupsrefutedthisresult.[185,188]
CASP8:CASP8geneislocalizedonchromosome2q3334andcodesforcaspase8.ThisgeneisalsoknownasFLICEorMCH5.Two
commonlyknownpolymorphismsintheCASP8genehavebeenwellstudied,namelyCASP8D302HandCASP86526Nins/del.[189]
Amongthese,onlyCASP86526Nins/del(rs3834129)polymorphismisassociatedwithsusceptibilitytocervicalcancer.[190]A
functionalpolymorphismofasixnucleotidedeletionofAGTAAGattheposition652ofthepromoterregionoftheCASP8gene
(CASP86526Nins/del)hasbeenidentified.Thissixnucleotidedeletiondestroysabindingelementfortranscriptionalactivator
stimulatoryprotein1(SP1)whichreducescapase8expressionleadingtodecreasedAICDinCTLs.[190]
TheinfluenceofCASP86526Nins/delpolymorphismoncervicalcancerwasinvestigatedandareducedriskofcervicalcancerwas
reportedwithCASP86526Ndel/del.[190]
Genesencodingdetoxifyingenzymes(CYP1A1,CYP2D6,GSTM1,GSTT1):Environmentalriskfactorshavebeenspeculatedtoplay
animportantroleinHPVinfectionandpersistencebymanyresearchers.Smokingisawellknownenvironmentalriskfactor[191]in
progressiontocervicalcancer,suggestingapossiblelinkwithallelicchangesatthegenesencodingfordetoxifyingenzymes.CYP1A1
andCYP2D6arephase1cytochromeP450enzymethatcatalyzethemodificationofvariousenzymesincludingcarcinogenicenzymes
andhelpthephase2enzymes,glutathioneStransferases(GSTfamily),toconverttoextractablecompounds.
CYP1A1:SeveralpolymorphismshavebeendescribedforCYP1A1,aTtoCchange(m2)inthe3noncodingregionofthegeneleading
toanMspIrestrictionsitehasbeenwellstudied.AnincreasedriskofdevelopingcervicalcancerwithCallele,C/CandT/Cgenotypeof
m2polymorphismcomparedtowildtypeT/Tgenotypewasobserved.[70,192,193]Noassociationofthispolymorphismwithdisease
severitywasobservedaswell.[177]Otherstudiesreportedm1polymorphism(G)andCYP1A1*3astheriskallelesforcervicalcancer.
[194,195]
CYP2D6:CYP2D6isclassifiedinwildtypehomozygousextensivemetabolizers(EM)carryingamutationofGtoAatintron3/exon4,
heterozygousextensivemetabolizers(HEM)carryingabasepairdeletioninexon5andpoormetabolizers(PM)withatotalgene
deletion.Thispolymorphismhasbeenstudiedincancerwithcontradictoryresults.[195,196]ItwasshownthatEMisasusceptibleallele
andgenotypeforhighgradeCINinwomenwhosmoke,butthesameisnottrueforprogressiontoSCC.[196]

GSTM1:GSTM1genotypeisacombinationofGSTM1*0,GSTM1*AandGSTM1*Balleles.GSTM1*0isalsocalledGSTM1null,
whichisadeletionofthegeneandnoexpressionofproteinforhomozygotes.Studieswiththispolymorphismshowedapositive
associationwithsusceptibilitytocervicalcancerandhighriskHPVinfectionandGSTM1nullgenotype,[72,193,197,198]whereasother
groupsfailedtofindanyassociation.[70,199201]
GSTT1:GSTT1geneplaysaroleinphasetwodetoxificationofcarcinogenspresentintobaccosmokeandalsoinpesticideslikehalo
methanesandmethylbromide.[195]Somestudieswiththispolymorphismoncervicalcancerpatientsfoundanassociationofthis
genotypewithincreasingriskofdevelopingcervicalcancerorHSIL[70,202204]ontheotherhand,somestudiesreportedno
associationwithcancerofthecervix.[193,195,198,202]
ThisreviewcompilesthemajorhostgeneticriskfactorsthathavebeenfoundassociatedandnotassociatedwithHPVinfectionand
progressiontocancerofthecervix.Zoodsmaetal,publishedametaanalysisofHLAgenesandothernonHLAcandidategenes.They
reviewed35publicationsforHLAgenesand32publicationsforTp53gene.AreviewarticlebyHildesheimetal,onHLAgenes
considered28publications.AnothermetaanalysisofTp53genereviewed37publications.Allthesereviewsconsideredpublicationsup
till2002.Thepresentreviewiswiderineverysenseasitconsidersagreaternumberofpublications.Thisisalsoanupdatedreviewof
hostgeneticsusceptibilitytocervicalcancercomparedtotheabovementionedreviews.Thisreviewalsoincludesmoregenes(suchas
Fas,FasL,CCR2V64IandIFN)thanreviewedbyZoodsmaetal.
Inconclusion,thisreviewshowsabroadpictureofhostgeneticdeterminantstoHPVinfection,differentstagesofneoplasiaand
progressiontocervicalcancer.Itisnotpossibletopinpointoneortwogenescausingseverityorconferringaprotectiveeffecttoa
complexdisorderlikecervicalcancer,ratherdependsondifferentgenesinvolvedindifferentpathwaysinadditiontothemaincausative
agent.Itisalsoevidentthatacomplexdiseaselikecervicalcancerdependsondifferentparametersandacriticalinteractionbetween
differentgenesandalsobetweengeneandenvironmentplayacrucialroleinthat.
Acknowledgments
IwouldliketothankProf.AnnaLiseWilliamson(InstituteofInfectiousDiseaseandMolecularMedicine,MedicalVirology,University
ofCapeTown)andDr.ColletDandara(InstituteofInfectiousDiseaseandMolecularMedicine,HumanGenetics,UniversityofCape
Town)foreditingandreviewingthevirologypartandthegeneticspartofthereviewrespectively.FundingwasprovidedbyUniversity
ofCapeTown,PoliomyelitisResearchFoundation(PRF)andNationalResearchFoundation(NRF),SouthAfrica.
Footnotes
SourceofSupport:UniversityofCapeTown,PoliomyelitisResearchFoundation(PRF)andNationalResearchFoundation(NRF),SouthAfrica.

ConflictofInterest:Nil.

References
1.CastellsagueXS,deAguadoS,LouieD,BruniKS,MunozL,DiazJ,etal.HPVandcervicalcancerintheworld2007report.
Vaccine.200726:S3.
2.ParkinDM.Globalcancerstatisticsintheyear2000.LancetOncol.20012:53343.[PubMed:11905707]
3.ParkinDM,BrayFI,DevesaSS.Cancerburdenintheyear2000:Theglobalpicture.EurJCancer.200137(Suppl8):S466.
[PubMed:11602373]
4.GallowayDA.Papillomavirusvaccinesinclinicaltrials.LancetInfectDis.20033:46975.[PubMed:12901889]
5.MagnussonPK,SparenP,GyllenstenUB.Geneticlinktocervicaltumours.Nature.1999400:2930.[PubMed:10403244]
6.HemminkiK,DongC,VaittinenP.Familialrisksincervicalcancer:Isthereahereditarycomponent?IntJCancer.199982:77581.
[PubMed:10446440]
7.ZhuM,ZhaoS.Candidategeneidentificationapproach:Progressandchallenges.IntJBiolSci.20073:4207.
[PMCID:PMC2043166][PubMed:17998950]
8.TaborHK,RischNJ,MyersRM.Candidategeneapproachesforstudyingcomplexgenetictraits:Practicalconsiderations.NatRev
Genet.20023:3917.[PubMed:11988764]
9.DugganKeenMF,KeatingPJ,StevensFR,SinnottP,SnijdersPJ,WalboomersJM,etal.ImmunogeneticfactorsinHPVassociated
cervicalcancer:Influenceondiseaseprogression.EurJImmunogenet.199623:27584.[PubMed:8858284]
10.HildesheimA,SchiffmanM,ScottDR,MartiD,KissnerT,ShermanME,etal.HumanleukocyteantigenclassI/IIallelesand
developmentofhumanpapillomavirusrelatedcervicalneoplasia:ResultsfromacasecontrolstudyconductedintheUnitedStates.
CancerEpidemiolBiomarkersPrev.19987:103541.[PubMed:9829713]
11.WangSS,WheelerCM,HildesheimA,SchiffmanM,HerreroR,BrattiMC,etal.HumanleukocyteantigenclassIandIIallelesand
riskofcervicalneoplasia:ResultsfromapopulationbasedstudyinCostaRica.JInfectDis.2001184:13104.[PubMed:11679920]
12.KrulEJ,SchipperRF,SchreuderGM,FleurenGJ,KenterGG,MeliefCJ.HLAandsusceptibilitytocervicalneoplasia.Hum
Immunol.199960:33742.[PubMed:10363725]

13.ChanPK,CheungJL,CheungTH,LinCK,TamAO,ChanDP,etal.HLABalleles,highriskHPVinfectionandriskforcervical
neoplasiainsouthernChinesewomen.IntJCancer.2006118:14305.[PubMed:16206270]
14.MontoyaL,SaizI,ReyG,VelaF,ClericiLarradetN.Cervicalcarcinoma:HumanpapillomavirusinfectionandHLAassociated
riskfactorsintheSpanishpopulation.EurJImmunogenet.199825:32937.[PubMed:9805655]
15.SilvaB,VargasAlarconG,ZunigaRamosJ,RodriguezReynaTS,HernandezMartinezB,OsnayaN,KofmanS,TorresLobaton
A,GranadosJ.GeneticfeaturesofMexicanwomenpredisposingtocanceroftheuterinecervix.HumPathol.199930:626628.
[PubMed:10374768]
16.TrimbleCL,PiantadosiS,GravittP,RonnettB,PizerE,ElkoA,etal.Spontaneousregressionofhighgradecervicaldysplasia:
EffectsofhumanpapillomavirustypeandHLAphenotype.ClinCancerRes.200511:471723.[PMCID:PMC3132609]
[PubMed:16000566]
17.CarreonJD,MartinMP,HildesheimA,GaoX,SchiffmanM,HerreroR,etal.HumanleukocyteantigenclassIandIIhaplotypes
andriskofcervicalcancer.TissueAntigens.200566:3214.[PubMed:16185329]
18.ChanDP,CheungTH,TamAO,CheungJL,YimSF,LoKW,etal.RiskassociationbetweenhumanleukocyteantigenAallele
andhighriskhumanpapillomavirusinfectionforcervicalneoplasiainChinesewomen.JInfectDis.2005192:174956.
[PubMed:16235173]
19.WangSS,HildesheimA,GaoX,SchiffmanM,HerreroR,BrattiMC,etal.Comprehensiveanalysisofhumanleukocyteantigen
classIallelesandcervicalneoplasiain3epidemiologicstudies.JInfectDis.2002186:598605.[PubMed:12195346]
20.WankR,ThomssenC.HighriskofsquamouscellcarcinomaofthecervixforwomenwithHLADQw3.Nature.1991352:7235.
[PubMed:1876187]
21.HellandA,BorresenAL,KaernJ,RonningenKS,ThorsbyE.HLAantigensandcervicalcarcinoma.Nature.1992356:23.
[PubMed:1538776]
22.WankR,SchendelDJ,ThomssenC.HLAantigensandcervicalcarcinoma.Nature.1992356:223.[PubMed:1538774]
23.DavidAL,TaylorGM,GokhaleD,AplinJD,SeifMW,TindallVR.HLADQB1*03andcervicalintraepithelialneoplasiatypeIII.
Lancet.1992340:52.[PubMed:1351625]
24.WankR,MeulenJT,LuandeJ,EberhardtHC,PawlitaM.Cervicalintraepithelialneoplasia,cervicalcarcinoma,andriskforpatients

withHLADQB1*0602,*301,*0303alleles.Lancet.1993341:1215.[PubMed:8098101]
25.HellandA,BorresenAL,KristensenG,RonningenKS.DQA1andDQB1genesinpatientswithsquamouscellcarcinomaofthe
cervix:Relationshiptohumanpapillomavirusinfectionandprognosis.CancerEpidemiolBiomarkersPrev.19943:47986.
[PubMed:8000298]
26.MehalWZ,LoYM,HerringtonCS,EvansMF,PapadopoulosMC,OdunisK,etal.Roleofhumanpapillomavirusindetermining
theHLAassociatedriskofcervicalcarcinogenesis.JClinPathol.199447:107781.[PMCID:PMC502196][PubMed:7876378]
27.GregoireL,LawrenceWD,KukurugaD,EisenbreyAB,LancasterWD.AssociationbetweenHLADQB1allelesandriskfor
cervicalcancerinAfricanAmericanwomen.IntJCancer.199457:5047.[PubMed:8181853]
28.OdunsiK,TerryG,HoL,BellJ,CuzickJ,GanesanTS.AssociationbetweenHLADQB1*03andcervicalintraepithelial
neoplasia.MolMed.19951:16171.[PMCID:PMC2229948][PubMed:8529095]
29.NawaA,NishiyamaY,KobayashiT,WakaharaY,OkamotoT,KikkawaF,etal.AssociationofhumanleukocyteantigenB1*03
withcervicalcancerinJapanesewomenaged35yearsandyounger.Cancer.199575:51821.[PubMed:7812922]
30.AppleRJ,BeckerTM,WheelerCM,ErlichHA.ComparisonofhumanleukocyteantigenDRDQdiseaseassociationsfoundwith
cervicaldysplasiaandinvasivecervicalcarcinoma.JNatlCancerInst.199587:42736.[PubMed:7861462]
31.OdunsiK,TerryG,HoL,BellJ,CuzickJ,GanesanTS.Susceptibilitytohumanpapillomavirusassociatedcervicalintraepithelial
neoplasiaisdeterminedbyspecificHLADRDQalleles.IntJCancer.199667:595602.[PubMed:8782644]
32.SanjeeviCB,HjelmstromP,HallmansG,WiklundF,LennerP,AngstromT,etal.DifferentHLADRDQhaplotypesare
associatedwithcervicalintraepithelialneoplasiaamonghumanpapillomavirustype16seropositiveandseronegativeSwedishwomen.
IntJCancer.199668:40914.[PubMed:8945607]
33.FerreraA,OlivoA,AlaezC,MelchersWJ,GorodezkyC.HLADOA1andDOB1lociinHonduranwomenwithcervicaldysplasia
andinvasivecervicalcarcinomaandtheirrelationshiptohumanpapillomavirusinfection.HumBiol.199971:36779.
[PubMed:10380373]
34.CuzickJ,TerryG,HoL,MonaghanJ,LopesA,ClarksonP,etal.AssociationbetweenhighriskHPVtypes,HLADRB1*and
DQB1*allelesandcervicalcancerinBritishwomen.BrJCancer.200082:134852.[PMCID:PMC2374489][PubMed:10755413]
35.NeumanRJ,HuettnerPC,LiL,MardisER,DuffyBF,WilsonRK,etal.AssociationbetweenDQB1andcervicalcancerinpatients

withhumanpapillomavirusandfamilycontrols.ObstetGynecol.200095:13440.[PubMed:10636516]
36.BeskowAH,JosefssonAM,GyllenstenUB.HLAclassIIallelesassociatedwithinfectionbyHPV16incervicalcancerinsitu.IntJ
Cancer.200193:81722.[PubMed:11519043]
37.DehaghaniAS,AmirzargarA,FarjadianS,GhaderiA.HLADQBlallelesandsusceptibilitytocervicalsquamouscellcarcinomain
SouthernIranianpatients.PatholOncolRes.20028:5861.[PubMed:11994765]
38.GhaderiM,WallinKL,WiklundF,ZakeLN,HallmansG,LennerP,etal.Riskofinvasivecervicalcancerassociatedwith
polymorphicHLADR/DQhaplotypes.IntJCancer.2002100:698701.[PubMed:12209609]
39.MatsumotoK,YasugiT,NakagawaS,OkuboM,HirataR,MaedaH,etal.Humanpapillomavirustype16E6variantsandHLA
classIIallelesamongJapanesewomenwithcervicalcancer.IntJCancer.2003106:91922.[PubMed:12918070]
40.EngelmarkM,BeskowA,MagnussonJ,ErlichH,GyllenstenU.AffectedsibpairanalysisofthecontributionofHLAclassIand
classIIlocitodevelopmentofcervicalcancer.HumMolGenet.200413:19518.[PubMed:15238505]
41.DaoDD,SierraTorresCH,RobazettiSC,deGomezMN,KonigR,LemaC,etal.HLADQB1andcervicalcancerinVenezuelan
women.GynecolOncol.200596:34954.[PubMed:15661220]
42.ZoodsmaM,NolteIM,SchipperM,OosteromE,vanderSteegeG,deVriesEG,etal.AnalysisoftheentireHLAregionin
susceptibilityforcervicalcancer:Acomprehensivestudy.JMedGenet.200542:e49.[PMCID:PMC1736118][PubMed:16061555]
43.SchiffMA,AppleRJ,LinP,NelsonJL,WheelerCM,BeckerTM.HLAallelesandriskofcervicalintraepithelialneoplasiaamong
SouthwesternAmericanIndianwomen.HumImmunol.200566:10506.[PubMed:16386646]
44.WuY,ChenY,LiL,CaoY,LiuZ,LiuB,etal.Polymorphicaminoacidsatcodons9and37ofHLADQB1allelesmayconfer
susceptibilitytocervicalcanceramongChinesewomen.IntJCancer.2006118:300611.[PubMed:16425277]
45.LemaC,FuesselHawsAL,LewisLR,RadyPL,LeeP,TurbatHerreraEA,etal.AssociationbetweenHLADQB1andcervical
dysplasiainVietnamesewomen.IntJGynecolCancer.200616:126977.[PubMed:16803516]
46.WuY,LiuB,LinW,XuY,LiL,ZhangY,etal.HPV16E6variantsandHLAclassIIpolymorphismamongChinesewomenwith
cervicalcancer.JMedVirol.200779:43946.[PubMed:17311339]
47.BhattacharyaP,SenguptaS.PredispositiontoHPV16/18relatedcervicalcancerbecauseofprolinehomozygosityatcodon72of

p53amongIndianwomenisinfluencedbyHLAB*07andhomozygosityofHLADQB1*03.TissueAntigens.200770:28393.
[PubMed:17767549]
48.BeskowAH,MobergM,GyllenstenUB.HLAclassIIallelecontrolofHPVloadincarcinomainsituofthecervixuteri.IntJ
Cancer.2005117:5104.[PubMed:15906352]
49.ChanPK,CheungJL,CheungTH,LinCK,SiuSS,YuMM,etal.HLADQB1polymorphismsandriskforcervicalcancer:A
casecontrolstudyinasouthernChinesepopulation.GynecolOncol.2007105:73641.[PubMed:17379283]
50.PengS,TrimbleC,WuL,PardollD,RodenR,HungCF,etal.HLADQB1*02restrictedHPV16E7peptidespecificCD4+T
cellimmuneresponsescorrelatewithregressionofHPV16associatedhighgradesquamousintraepitheliallesions.ClinCancerRes.
200713:247987.[PMCID:PMC3181117][PubMed:17438108]
51.ClimentC,NazarioCM,UmpierreS,QuinteroM,GorbeaS.MajorhistocompatibilitycomplexclassIIpolymorphismsandriskof
cervicalcancerinPuertoRicanwomen.PRHealthSciJ.200726:97101.[PubMed:17722421]
52.SastreGarauX,LosteMN,VincentSalomonA,FavreM,MouretE,delaRochefordiereA,etal.DecreasedfrequencyofHLA
DRB113allelesinFrenchwomenwithHPVpositivecarcinomaofthecervix.IntJCancer.199669:15964.[PubMed:8682580]
53.GostoutBS,PodratzKC,McGovernRM,PersingDH.Cervicalcancerinolderwomen:Amolecularanalysisofhuman
papillomavirustypes,HLAtypes,andp53mutations.AmJObstetGynecol.1998179:5661.[PubMed:9704765]
54.MaciagPC,SchlechtNF,SouzaPS,FrancoEL,VillaLL,PetzlErlerML.MajorhistocompatibilitycomplexclassIIpolymorphisms
andriskofcervicalcancerandhumanpapillomavirusinfectioninBrazilianwomen.CancerEpidemiolBiomarkersPrev.20009:1183
91.[PubMed:11097225]
55.CervantesJ,LemaC,ValentinaHurtadoL,AndradeR,HurtadoGomezL,TorricoL,etal.HLADRB1*1602alleleispositively
associatedwithHPVcervicalinfectioninBolivianAndeanwomen.HumImmunol.200364:8905.[PubMed:12941545]
56.SastreGarauX,CartierI,JourdanDaSilvaN,DeCremouxP,LepageV,CharronD.Regressionoflowgradecervical
intraepithelialneoplasiainpatientswithHLADRB1*13genotype.ObstetGynecol.2004104:7515.[PubMed:15458897]
57.MahmudSM,RobinsonK,RichardsonH,TellierPP,FerenczyAS,RogerM,etal.HLApolymorphismsandcervicalhuman
PapillomavirusinfectioninacohortofMontrealUniversitystudents.JInfectDis.2007196:8290.[PubMed:17538887]
58.ChanPK,CheungTH,LinCK,SiuSS,YimSF,LoKW,etal.AssociationbetweenHLADRB1polymorphism,highriskHPV

infectionandcervicalneoplasiainsouthernChinese.JMedVirol.200779:9706.[PubMed:17516530]
59.VandenveldeC,DeFoorM,vanBeersD.HLADOB1*03andcervicalintraepithelialneoplasiagradesIIII.Lancet.1993341:442.
[PubMed:8094211]
60.WuY,LiuB,LinW,XuY,LiL,ZhangY,etal.HumanleukocyteantigenclassIIallelesandriskofcervicalcancerinChina.Hum
Immunol.200768:192200.[PubMed:17349874]
61.AppleRJ,ErlichHA,KlitzW,ManosMM,BeckerTM,WheelerCM.HLADRDQassociationswithcervicalcarcinomashow
papillomavirustypespecificity.NatGenet.19946:15762.[PubMed:8162070]
62.AllenM,KalantariM,YlitaloN,PetterssonB,HagmarB,ScheibenpflugL,etal.HLADQDRhaplotypeandsusceptibilityto
cervicalcarcinoma:IndicationsofincreasedriskfordevelopmentofcervicalcarcinomainindividualsinfectedwithHPV18.Tissue
Antigens.199648:327.[PubMed:8864172]
63.HellandA,OlsenAO,GjoenK,AkselsenHE,SauerT,MagnusP,etal.Anincreasedriskofcervicalintraepithelialneoplasia
gradeIIIIIamonghumanpapillomaviruspositivepatientswiththeHLADQA1*0102DQB1*0602haplotype:Apopulationbased
casecontrolstudyofNorwegianwomen.IntJCancer.199876:1924.[PubMed:9533756]
64.ZehbeI,TachezyR,MytilineosJ,VoglinoG,MikyskovaI,DeliusH,etal.Humanpapillomavirus16E6polymorphismsincervical
lesionsfromdifferentEuropeanpopulationsandtheircorrelationwithhumanleukocyteantigenclassIIhaplotypes.IntJCancer.
200194:7116.[PubMed:11745467]
65.DeAraujoSouzaPS,VillaLL.Geneticsusceptibilitytoinfectionwithhumanpapillomavirusanddevelopmentofcervicalcancerin
womeninBrazil.MutatRes.2003544:37583.[PubMed:14644340]
66.YangYC,ChangCL,ChenML.Effectofp53polymorphismonthesusceptibilityofcervicalcancer.GynecolObstetInvest.
200151:197201.[PubMed:11306909]
67.StoreyA,ThomasM,KalitaA,HarwoodC,GardiolD,MantovaniF,etal.Roleofap53polymorphisminthedevelopmentof
humanpapillomavirusassociatedcancer.Nature.1998393:22934.[PubMed:9607760]
68.AnderssonS,RylanderE,StrandA,SallstromJ,WilanderE.Thesignificanceofp53codon72polymorphismforthedevelopment
ofcervicaladenocarcinomas.BrJCancer.200185:11536.[PMCID:PMC2375157][PubMed:11710828]
69.ZehbeI,VoglinoG,WilanderE,GentaF,TommasinoM.Codon72polymorphismofp53anditsassociationwithcervicalcancer.

Lancet.1999354:2189.[PubMed:10421306]
70.KimJW,LeeCG,ParkYG,KimKS,KimIK,SohnYW,etal.Combinedanalysisofgermlinepolymorphismsofp53,GSTM1,
GSTT1,CYP1A1,andCYP2E1:Relationtotheincidencerateofcervicalcarcinoma.Cancer.200088:208291.[PubMed:10813720]
71.JeeSH,LeeJE,ParkJS.Polymorphismofcodon72ofp53andenvironmentalfactorsinthedevelopmentofcervicalcancer.IntJ
GynaecolObstet.200380:6970.[PubMed:12527466]
72.LeeSA,KimJW,RohJW,ChoiJY,LeeKM,YooKY,etal.GeneticpolymorphismsofGSTM1,p21,p53andHPVinfection
withcervicalcancerinKoreanwomen.GynecolOncol.200493:148.[PubMed:15047208]
73.MakniH,FrancoEL,KaianoJ,VillaLL,LabrecqueS,DudleyR,etal.P53polymorphismincodon72andriskofhuman
papillomavirusinducedcervicalcancer:Effectofinterlaboratoryvariation.IntJCancer.200087:52833.[PubMed:10918193]
74.DosSantosOliveiraLdoH,FernandezAdeP,XavierBL,MachadoRodriguesEdeV,CavalcantiSM.Analysisofthep53gene
andpapillomavirusdetectioninsmearsfromcervicallesions.SaoPauloMedJ.2002120:202.[PubMed:11836549]
75.VanDuinM,SnijdersPJ,VossenMT,KlaassenE,VoorhorstF,VerheijenRH,etal.Analysisofhumanpapillomavirustype16E6
variantsinrelationtop53codon72polymorphismgenotypesincervicalcarcinogenesis.JGenVirol.200081:31725.
[PubMed:10644829]
76.DokianakisDN,SpandidosDA.P53codon72polymorphismasariskfactorinthedevelopmentofHPVassociatedcervicalcancer.
MolCellBiolResCommun.20003:1114.[PubMed:10775508]
77.KlugSJ,WilmotteR,SantosC,AlmonteM,HerreroR,GuerreroI,etal.TP53polymorphism,HPVinfection,andriskofcervical
cancer.CancerEpidemiolBiomarkersPrev.200110:100912.[PubMed:11535556]
78.PegoraroRJ,RomL,LanningPA,MoodleyM,NaikerS,MoodleyJ.P53codon72polymorphismandhumanpapillomavirustype
inrelationtocervicalcancerinSouthAfricanwomen.IntJGynecolCancer.200212:3838.[PubMed:12144687]
79.SaranathD,KhanZ,TandleAT,DedhiaP,SharmaB,ContractorR,etal.HPV16/18prevalenceincervicallesions/cancersandp53
genotypesincervicalcancerpatientsfromIndia.GynecolOncol.200286:15762.[PubMed:12144822]
80.NagpalJK,SahniS,DasBR.P53codon72polymorphismandsusceptibilitytodevelopmentofhumanpapillomavirusassociated
cervicalcancerinIndianwomen.EurJClinInvest.200232:9438.[PubMed:12534455]

81.MitraS,MisraC,SinghRK,PandaCK,RoychoudhuryS.Associationofspecificgenotypeandhaplotypeofp53genewithcervical
cancerinIndia.JClinPathol.200558:2631.[PMCID:PMC1770549][PubMed:15623478]
82.ArbelAlonS,MenczerJ,FeldmanN,GlezermanM,YereminL,FriedmanE.Codon72polymorphismofp53inIsraeliJewish
cervicalcancerpatientsandhealthywomen.IntJGynecolCancer.200212:7414.[PubMed:12445252]
83.QieM,ZhangY,WuJ.Studyontherelationshipbetweencervicalcancerandp53codon72polymorphism.HuaXiYiKeDaXue
XueBao.200233:2745.[PubMed:12575207]
84.OjedaJM,AmpueroS,RojasP,PradoR,AllendeJE,BartonSA,etal.p53codon72polymorphismandriskofcervicalcancer.
BiolRes.200336:27983.[PubMed:14513722]
85.WongYF,ChungTK,CheungTH,NoboriT,HamptonGM,WangVW,etal.p53polymorphismandhumanpapillomavirus
infectioninHongKongwomenwithcervicalcancer.GynecolObstetInvest.200050:603.[PubMed:10895031]
86.MinaguchiT,KanamoriY,MatsushimaM,YoshikawaH,TaketaniY,NakamuraY.Noevidenceofcorrelationbetween
polymorphismatcodon72ofp53andriskofcervicalcancerinJapanesepatientswithhumanpapillomavirus16/18infection.Cancer
Res.199858:45856.[PubMed:9788606]
87.NishikawaA,FujimotoT,AkutagawaN,IwasakiM,TakeuchiM,FujinagaK,etal.p53Polymorphism(codon72)hasno
correlationwiththedevelopmentandtheclinicalfeaturesofcervicalcancer.IntJGynecolCancer.200010:4027.[PubMed:11240705]
88.JosefssonAM,MagnussonPK,YlitaloN,QuarforthTubbinP,PontenJ,AdamiHO,etal.p53polymorphismandriskofcervical
cancer.Nature.1998396:531.authorreply532.[PubMed:9859988]
89.GustafssonAC,GuoZ,HuX,AhmadianA,BrodinB,NilssonA,etal.HPVrelatedcancersusceptibilityandp53codon72
polymorphism.ActaDermVenereol.200181:1259.[PubMed:11501650]
90.MalcolmEK,BaberGB,BoydJC,StolerMH.Polymorphismatcodon72ofp53isnotassociatedwithcervicalcancerrisk.Mod
Pathol.200013:3738.[PubMed:10786802]
91.MadeleineMM,SheraK,SchwartzSM,DalingJR,GallowayDA,WipfGC,etal.Thep53Arg72Propolymorphism,human
papillomavirus,andinvasivesquamouscellcervicalcancer.CancerEpidemiolBiomarkersPrev.20009:2257.[PubMed:10698487]
92.InserraP,AbrahamsenM,PapenfussM,GiulianoAR.EthnicvariationoftheP53codon72polymorphism,HPVpersistence,and
cervicalcancerrisk.IntJSTDAIDS.200314:8004.[PubMed:14678586]

93.RosenthalAN,RyanA,AlJehaniRM,StoreyA,HarwoodCA,JacobsIJ.p53codon72polymorphismandriskofcervicalcancer
inUK.Lancet.1998352:8712.[PubMed:9742979]
94.LanhamS,CampbellI,WattP,GornallR.p53polymorphismandriskofcervicalcancer.Lancet.1998352:1631.
[PubMed:9843136]
95.GiannoudisA,GrahamDA,SouthernSA,HerringtonCS.p53codon72ARG/PROpolymorphismisnotrelatedtoHPVtypeor
lesiongradeinlowandhighgradesquamousintraepitheliallesionsandinvasivesquamouscarcinomaofthecervix.IntJCancer.
199983:669.[PubMed:10449610]
96.BradyCS,DugganKeenMF,DavidsonJA,VarleyJM,SternPL.Humanpapillomavirustype16E6variantsincervicalcarcinoma:
Relationshiptohostgeneticfactorsandclinicalparameters.JGenVirol.199980:323340.[PubMed:10567656]
97.HayesVM,HofstraRM,BuysCH,HollemaH,vanderZeeAG.Homozygousarginine72inwildtypep53andriskofcervical
cancer.Lancet.1998352:1756.[PubMed:9848359]
98.GovanVA,LoubserS,SalehD,HoffmanM,WilliamsonAL.Norelationshipobservedbetweenhumanp53codon72genotype
andHPVassociatedcervicalcancerinapopulationgroupwithalowarginine72allelefrequency.IntJImmunogenet.200734:2137.
[PubMed:17504512]
99.HellandA,BorresenDaleAL.p53polymorphismandcervicalcancer.Lancet.1999354:15612.[PubMed:10551531]
100.NganHY,LiuVW,LiuSS.RiskofcervicalcancerisnotincreasedinChinesecarryinghomozygousarginineatcodon72ofp53.
BrJCancer.199980:18289.[PMCID:PMC2374271][PubMed:10468305]
101.HouMM,XiMR,CaoZY,YangKX,SunZL.P53codon72polymorphismincervicalcancersanditscorrelationwith
HPV16,18E6.SichuanDaXueXueBaoYiXueBan.200637:4047.[PubMed:16761419]
102.MinminH,MingrongX,ZeyiC,KaixuanY,ZhilinS.Analysisofp53codon72polymorphismanditsassociationwithhuman
papillomavirus16and18E6inChinesecervicallesions.IntJGynecolCancer.200616:20048.[PubMed:17177838]
103.YamashitaT,YaginumaY,SaitohY,KawaiK,KurakaneT,HayashiH,etal.Codon72polymorphismofp53asariskfactorfor
patientswithhumanpapillomavirusassociatedsquamousintraepitheliallesionsandinvasivecanceroftheuterinecervix.Carcinogenesis.
199920:17336.[PubMed:10469618]
104.NiwaY,HamajimaN,AtsutaY,YamamotoK,TamakoshiA,SaitoT,etal.Geneticpolymorphismsofp73G4C14toA4T14at

exon2andp53Arg72ProandtheriskofcervicalcancerinJapanese.CancerLett.2004205:5560.[PubMed:15036661]
105.TachezyR,MikyskovaI,SalakovaM,VanRanstM.Correlationbetweenhumanpapillomavirusassociatedcervicalcancerand
p53codon72arginine/prolinepolymorphism.HumGenet.1999105:5646.[PubMed:10647890]
106.BaekWK,ChoJW,SuhSI,SuhMH,ShinDH,ChoCH,etal.p53codon72polymorphismandriskofcervicalcarcinomain
Koreanwomen.JKoreanMedSci.200015:657.[PMCID:PMC3054593][PubMed:10719811]
107.KimJW,RohJW,ParkNH,SongYS,KangSB,LeeHP.PolymorphismofTP53codon72andtheriskofcervicalcanceramong
Koreanwomen.AmJObstetGynecol.2001184:558.[PubMed:11174479]
108.TentiP,VesentiniN,RondoSpaudoM,ZappatoreR,MiglioraP,CarnevaliL,etal.p53codon72polymorphismdoesnotaffect
theriskofcervicalcancerinpatientsfromnorthernItaly.CancerEpidemiolBiomarkersPrev.20009:4358.[PubMed:10794489]
109.CenciM,FrenchD,PisaniT,AlderisioM,LombardiAM,MarcheseR,etal.p53polymorphismatcodon72isnotariskfactorfor
cervicalcarcinogenesisincentralItaly.AnticancerRes.200323:13857.[PubMed:12820398]
110.ComarM,MolinGD,GuaschinoS,CampelloC.p53atcodon72polymorphism,humanpapillomavirusinfectionandcervical
lesions:AcrosssectionalstudyfromnortheasternItaly.EurJObstetGynecolReprodBiol.2004114:2104.[PubMed:15140517]
111.KuceraE,TongD,ReinthallerA,LeodolterS,ZeillingerR,SliutzG.p53polymorphismatcodon72doesitconstituteariskfor
squamousintraepitheliallesionsandinvasivecancerofthecervixinCentralEuropeans?WienKlinWochenschr.2000112:81720.
[PubMed:11072671]
112.PillaiMR,SreevidyaS,PollockBH,JayaprakashPG,HermanB.Polymorphismatcodon72ofp53,humanpapillomavirus,and
cervicalcancerinSouthIndia.JCancerResClinOncol.2002128:62731.[PubMed:12458344]
113.KatiyarS,ThelmaBK,MurthyNS,HedauS,JainN,GopalkrishnaV,etal.Polymorphismofthep53codon72Arg/Proandthe
riskofHPVtype16/18associatedcervicalandoralcancerinIndia.MolCellBiochem.2003252:11724.[PubMed:14577584]
114.AbbaMC,VillaverdeLM,GomezMA,DuloutFN,LaguensMR,GolijowCD.Thep53codon72genotypesinHPVinfection
andcervicaldisease.EurJObstetGynecolReprodBiol.2003109:636.[PubMed:12818446]
115.BrennaSM,SilvaID,ZeferinoLC,PereiraJS,MartinezEZ,SyrjanenKJ.PrognosticvalueofP53codon72polymorphismin
invasivecervicalcancerinBrazil.GynecolOncol.200493:37480.[PubMed:15099948]

116.SettheethamIshidaW,SingtoY,YuenyaoP,TassaneeyakulW,KanjanavirojkulN,IshidaT.Contributionofepigeneticrisk
factorsbutnotp53codon72polymorphismtothedevelopmentofcervicalcancerinNortheasternThailand.CancerLett.2004210:205
11.[PubMed:15183536]
117.SettheethamIshidaW,KanjanavirojkulN,KularbkaewC,IshidaT.Humanpapillomavirusgenotypesandthep53codon72
polymorphismincervicalcancerofNortheasternThailand.MicrobiolImmunol.200549:41721.[PubMed:15905603]
118.LiCY,LiuJH,HuangBJ.CorrelationbetweenP53codon72polymorphismandtumorigenesisofcervicalcancer.AiZheng.
200423:13969.[PubMed:15566643]
119.WilsonNS,DixitV,AshkenaziA.Deathreceptorsignaltransducers:Nodesofcoordinationinimmunesignallingnetworks.Nat
Immunol.200910:34855.[PubMed:19295631]
120.CarrollMC,KatzmanP,AlicotEM,KollerBH,GeraghtyDE,OrrHT,etal.Linkagemapofthehumanmajorhistocompatibility
complexincludingthetumornecrosisfactorgenes.ProcNatlAcadSciUSA.198784:85359.[PMCID:PMC299579]
[PubMed:2825194]
121.BeutlerB,CeramiA.Thebiologyofcachectin/TNF:Aprimarymediatorofthehostresponse.AnnuRevImmunol.19897:625
55.[PubMed:2540776]
122.ArdizzoiaA,LissoniP,BrivioF,TisiE,PeregoMS,GrassiMG,etal.Tumornecrosisfactorinsolidtumors:Increasedblood
levelsinthemetastaticdisease.JBiolRegulHomeostAgents.19926:1037.[PubMed:1492596]
123.GhaderiM,NikitinaL,PeacockCS,HjelmstromP,HallmansG,WiklundF,etal.Tumornecrosisfactora11andDR15DQ6
(B*0602)haplotypeincreasetheriskforcervicalintraepithelialneoplasiainhumanpapillomavirus16seropositivewomeninNorthern
Sweden.CancerEpidemiolBiomarkersPrev.20009:106770.[PubMed:11045789]
124.StanczukGA,SibandaEN,TswanaSA,BergstromS.Polymorphismatthe308promoterpositionofthetumornecrosisfactor
alpha(TNFalpha)geneandcervicalcancer.IntJGynecolCancer.200313:14853.[PubMed:12657115]
125.GovanVA,ConstantD,HoffmanM,WilliamsonAL.Theallelicdistributionof308TumorNecrosisFactoralphagene
polymorphisminSouthAfricanwomenwithcervicalcancerandcontrolwomen.BMCCancer.20066:24.[PMCID:PMC1397852]
[PubMed:16438713]
126.AbrahamssonJ,CarlssonB,MellanderL.Tumornecrosisfactoralphainmalignantdisease.AmJPediatrHematolOncol.

199315:3649.[PubMed:8214357]
127.UdalovaIA,NedospasovSA,WebbGC,ChaplinDD,TuretskayaRL.HighlyinformativetypingofthehumanTNFlocususing
sixadjacentpolymorphicmarkers.Genomics.199316:1806.[PubMed:8486354]
128.ZwirnerNW,FernandezVinaMA,StastnyP.MICA,anewpolymorphicHLArelatedantigen,isexpressedmainlyby
keratinocytes,endothelialcells,andmonocytes.Immunogenetics.199847:13948.[PubMed:9396860]
129.GrohV,SteinleA,BauerS,SpiesT.RecognitionofstressinducedMHCmoleculesbyintestinalepithelialgammadeltaTcells.
Science.1998279:173740.[PubMed:9497295]
130.OtaM,KatsuyamaY,MizukiN,AndoH,FurihataK,OnoS,etal.Trinucleotiderepeatpolymorphismwithinexon5oftheMICA
gene(MHCclassIchainrelatedgeneA):AllelefrequencydataintheninepopulationgroupsJapanese,NorthernHan,Hui,Uygur,
Kazakhstan,Iranian,SaudiArabian,GreekandItalian.TissueAntigens.199749:44854.[PubMed:9174136]
131.BahramS,BresnahanM,GeraghtyDE,SpiesT.AsecondlineageofmammalianmajorhistocompatibilitycomplexclassIgenes.
ProcNatlAcadSciUSA.199491:625963.[PMCID:PMC44180][PubMed:8022771]
132.SantosAM,SousaH,PintoD,PortelaC,PereiraD,CatarinoR,etal.LinkingTP53codon72andP21nt590genotypestothe
developmentofcervicalandovariancancer.EurJCancer.200642:95863.[PubMed:16542834]
133.ChedidM,MichieliP,LengelC,HuppiK,GivolD.Asinglenucleotidesubstitutionatcodon31(Ser/Arg)definesapolymorphism
inahighlyconservedregionofthep53induciblegeneWAF1/CIP1.Oncogene.19949:30214.[PubMed:8084608]
134.SunY,HildesheimA,LiH,LiY,ChenJY,ChengYJ,etal.Nopointmutationbutacodon31ser>argpolymorphismofthe
WAF1/CIP1/p21tumorsuppressorgeneinnasopharyngealcarcinoma(NPC):ThepolymorphismdistinguishesCaucasiansfrom
Chinese.CancerEpidemiolBiomarkersPrev.19954:2617.[PubMed:7606201]
135.RohJ,KimM,KimJ,ParkN,SongY,KangS,etal.Polymorphismsincodon31ofp21andcervicalcancersusceptibilityin
Koreanwomen.CancerLett.2001165:5962.[PubMed:11248419]
136.HarimaY,SawadaS,NagataK,SougawaM,OstapenkoV,OhnishiT.PolymorphismoftheWAF1geneisrelatedto
susceptibilitytocervicalcancerinJapanesewomen.IntJMolMed.20017:2614.[PubMed:11179504]
137.MooreKW,OGarraA,deWaalMalefytR,VieiraP,MosmannTR.Interleukin10.AnnuRevImmunol.199311:16590.
[PubMed:8386517]

138.DeWaalMalefytR,AbramsJ,BennettB,FigdorCG,deVriesJE.Interleukin10(IL10)inhibitscytokinesynthesisbyhuman
monocytes:AnautoregulatoryroleofIL10producedbymonocytes.JExpMed.1991174:120920.[PMCID:PMC2119001]
[PubMed:1940799]
139.ChangCH,FurueM,TamakiK.B71expressionofLangerhanscellsisupregulatedbyproinflammatorycytokines,andisdown
regulatedbyinterferongammaorbyinterleukin10.EurJImmunol.199525:3948.[PubMed:7533084]
140.ClericiM,MerolaM,FerrarioE,TrabattoniD,VillaML,StefanonB,etal.Cytokineproductionpatternsincervicalintraepithelial
neoplasia:Associationwithhumanpapillomavirusinfection.JNatlCancerInst.199789:24550.[PubMed:9017005]
141.ChopraV,DinhTV,HanniganEV.Circulatingserumlevelsofcytokinesandangiogenicfactorsinpatientswithcervicalcancer.
CancerInvest.199816:1529.[PubMed:9541628]
142.SzokeK,SzalmasA,SzladekG,VeressG,GergelyL,TothFD,etal.IL10promoternt1082A/Gpolymorphismandhuman
papillomavirusinfectionincytologicabnormalitiesoftheuterinecervix.JInterferonCytokineRes.200424:24551.
[PubMed:15144570]
143.TurnerDM,WilliamsDM,SankaranD,LazarusM,SinnottPJ,HutchinsonIV.Aninvestigationofpolymorphisminthe
interleukin10genepromoter.EurJImmunogenet.199724:18.[PubMed:9043871]
144.StanczukGA,SibandaEN,PerreyC,ChiraraM,PravicaV,HutchinsonIV,etal.Canceroftheuterinecervixmaybesignificantly
associatedwithagenepolymorphismcodingforincreasedIL10production.IntJCancer.200194:7924.[PubMed:11745479]
145.RohJW,KimMH,SeoSS,KimSH,KimJW,ParkNH,etal.Interleukin10promoterpolymorphismsandcervicalcancerriskin
Koreanwomen.CancerLett.2002184:5763.[PubMed:12104048]
146.GovanVA,CarraraHR,SachsJA,HoffmanM,StanczukGA,WilliamsonAL.EthnicdifferencesinallelicdistributionofIFNgin
SouthAfricanwomenbutnolinkwithcervicalcancer.JCarcinog.20032:3.[PMCID:PMC161806][PubMed:12809559]
147.ZoodsmaM,NolteIM,SchipperM,OosteromE,vanderSteegeG,deVriesEG,etal.Interleukin10andFaspolymorphismsand
susceptibilityfor(pre)neoplasticcervicaldisease.IntJGynecolCancer.200515(Suppl3):28290.[PubMed:16343245]
148.FarzanehF,RobertsS,MandalD,OllierB,WintersU,KitchenerHC,etal.TheIL101082Gpolymorphismisassociatedwith
clearanceofHPVinfection.BJOG.2006113:9614.[PubMed:16907941]
149.GoyetteP,SumnerJS,MilosR,DuncanAM,RosenblattDS,MatthewsRG,etal.Humanmethylenetetrahydrofolatereductase:

IsolationofcDNAmappingandmutationidentification.NatGenet.19947:551.[PubMed:7951330]
150.HarmonDL,WoodsideJV,YarnellJW,McMasterD,YoungIS,McCrumEE,etal.Thecommonthermolabilevariantof
methylenetetrahydrofolatereductaseisamajordeterminantofmildhyperhomocysteinaemia.QJM.199689:5717.[PubMed:8935478]
151.StevensonRE,SchwartzCE,DuYZ,AdamsMJ.,JrDifferencesinmethylenetetrahydrofolatereductasegenotypefrequencies,
betweenWhitesandBlacks.AmJHumGenet.199760:22930.[PMCID:PMC1712549][PubMed:8981967]
152.GerhardDS,NguyenLT,ZhangZY,BoreckiIB,ColemanBI,RaderJS.Arelationshipbetweenmethylenetetrahydrofolate
reductasevariantsandthedevelopmentofinvasivecervicalcancer.GynecolOncol.200390:5605.[PubMed:13678724]
153.PiyathilakeCJ,MacalusoM,JohanningGL,WhitesideM,HeimburgerDC,GiulianoA.Methylenetetrahydrofolatereductase
(MTHFR)polymorphismincreasestheriskofcervicalintraepithelialneoplasia.AnticancerRes.200020:17517.[PubMed:10928104]
154.GoodmanMT,McDuffieK,HernandezB,WilkensLR,BertramCC,KilleenJ,etal.Associationofmethylenetetrahydrofolate
reductasepolymorphismC677Tanddietaryfolatewiththeriskofcervicaldysplasia.CancerEpidemiolBiomarkersPrev.
200110:127580.[PubMed:11751445]
155.SullJW,JeeSH,YiS,LeeJE,ParkJS,KimS,etal.TheeffectofmethylenetetrahydrofolatereductasepolymorphismC677Ton
cervicalcancerinKoreanwomen.GynecolOncol.200495:55763.[PubMed:15581963]
156.ZoodsmaM,NolteIM,SchipperM,OosteromE,vanderSteegeG,deVriesEG,etal.Methylenetetrahydrofolatereductase
(MTHFR)andsusceptibilityfor(pre)neoplasticcervicaldisease.HumGenet.2005116:24754.[PubMed:15635481]
157.LambropoulosAF,AgorastosT,FokaZJ,ChrisafiS,ConstantinidisTC,BontisJ,etal.Methylenetetrahydrofolatereductase
polymorphismC677Tisnotassociatedtotheriskofcervicaldysplasia.CancerLett.2003191:18791.[PubMed:12618332]
158.HenaoOL,PiyathilakeCJ,WaterborJW,FunkhouserE,JohanningGL,HeimburgerDC,etal.Womenwithpolymorphismsof
methylenetetrahydrofolatereductase(MTHFR)andmethioninesynthase(MS)arelesslikelytohavecervicalintraepithelialneoplasia
(CIN)2or3.IntJCancer.2005113:9917.[PubMed:15514969]
159.PiyathilakeCJ,AzradM,MacalusoM,JohanningGL,CornwellPE,PartridgeEE,etal.ProtectiveassociationofMTHFR
polymorphismoncervicalintraepithelialneoplasiaismodifiedbyriboflavinstatus.Nutrition.200723:22935.[PMCID:PMC2025704]
[PubMed:17303386]
160.BilliauA,HeremansH,VermeireK,MatthysP.Immunomodulatorypropertiesofinterferongamma:Anupdate.AnnNYAcad

Sci.1998856:2232.[PubMed:9917861]
161.PravicaV,PerreyC,StevensA,LeeJH,HutchinsonIV.AsinglenucleotidepolymorphisminthefirstintronofthehumanIFN
gammagene:AbsolutecorrelationwithapolymorphicCAmicrosatellitemarkerofhighIFNgammaproduction.HumImmunol.
200061:8636.[PubMed:11053629]
162.KleineLowinskiK,RheinwaldJG,FichorovaRN,AndersonDJ,BasileJ,MungerK,etal.Selectivesuppressionofmonocyte
chemoattractantprotein1expressionbyhumanpapillomavirusE6andE7oncoproteinsinhumancervicalepithelialandepidermalcells.
IntJCancer.2003107:40715.[PubMed:14506741]
163.GerardC,RollinsBJ.Chemokinesanddisease.NatImmunol.20012:10815.[PubMed:11175802]
164.MantovaniA,BottazziB,ColottaF,SozzaniS,RucoL.Theoriginandfunctionoftumorassociatedmacrophages.Immunol
Today.199213:26570.[PubMed:1388654]
165.RiethdorfL,RiethdorfS,GutzlaffK,PrallF,LoningT.Differentialexpressionofthemonocytechemoattractantprotein1genein
humanpapillomavirus16infectedsquamousintraepitheliallesionsandsquamouscellcarcinomasofthecervixuteri.AmJPathol.
1996149:146976.[PMCID:PMC1865287][PubMed:8909236]
166.KleineLowinskiK,GillitzerR,KuhneHeidR,RoslF.Monocytechemoattractantprotein1(MCP1)geneexpressionincervical
intraepithelialneoplasiasandcervicalcarcinomas.IntJCancer.199982:611.[PubMed:10360812]
167.LoannidisJP,RosenbergPS,GoedertJJ,AshtonLJ,BenfieldTL,BuchbinderSP,etal.EffectsofCCR5Delta32,CCR264I,and
SDF13AallelesonHIV1diseaseprogression:Aninternationalmetaanalysisofindividualpatientdata.AnnInternMed.
2001135:78295.[PubMed:11694103]
168.SmithMW,DeanM,CarringtonM,WinklerC,HuttleyGA,LombDA,etal.ContrastinggeneticinfluenceofCCR2andCCR5
variantsonHIV1infectionanddiseaseprogression.HemophiliaGrowthandDevelopmentStudy(HGDS),MulticenterAIDSCohort
Study(MACS),MulticenterHemophiliaCohortStudy(MHCS),SanFranciscoCityCohort(SFCC),ALIVEStudy.Science.
1997277:95965.[PubMed:9252328]
169.MulherinSA,OBrienTR,IoannidisJP,GoedertJJ,BuchbinderSP,CoutinhoRA,etal.EffectsofCCR5Delta32andCCR264I
allelesonHIV1diseaseprogression:Theprotectionvarieswithdurationofinfection.AIDS.200317:37787.[PubMed:12556692]
170.DomsRW,PeiperSC.Unwelcomedguestswithmasterkeys:HowHIVuseschemokinereceptorsforcellularentry.Virology.

1997235:17990.[PubMed:9281497]
171.MiyagishiR,NiinoM,FukazawaT,YabeI,KikuchiS,TashiroK.CCchemokinereceptor2genepolymorphisminJapanese
patientswithmultiplesclerosis.JNeuroimmunol.2003145:1358.[PubMed:14644039]
172.ZafiropoulosA,CrikasN,PassamAM,SpandidosDA.SignificantinvolvementofCCR264IandCXCL123ainthedevelopment
ofsporadicbreastcancer.JMedGenet.200441:e59.[PMCID:PMC1735773][PubMed:15121787]
173.ChatterjeeK,DandaraC,HoffmanM,WilliamsonAL.CCR2V64Ipolymorphismisassociatedwithincreasedriskofcervical
cancerbutnotwithHPVinfectionorprecancerouslesionsinAfricanwomen.BMCCancer.201010:278.[PMCID:PMC2893113]
[PubMed:20537184]
174.CoelhoA,MatosA,CatarinoR,PintoD,SousaH,PereiraD,etal.TheinfluenceofchemokinereceptorCCR2genotypesinthe
routetocervicalcarcinogenesis.GynecolObstetInvest.200764:20812.[PubMed:17664883]
175.CoelhoA,MatosA,CatarinoR,PintoD,PereiraD,LopesC,etal.ProtectiveroleofthepolymorphismCCR264Iinthe
progressionfromsquamousintraepitheliallesionstoinvasivecervicalcarcinoma.GynecolOncol.200596:7604.[PubMed:15721423]
176.ZhengB,WiklundF,GharizadehB,SadatM,GambelungheG,HallmansG,etal.Geneticpolymorphismofchemokinereceptors
CCR2andCCR5inSwedishcervicalcancerpatients.AnticancerRes.200626:366974.[PubMed:17094383]
177.IvanssonEL,GustavssonIM,MagnussonJJ,SteinerLL,MagnussonPK,ErlichHA,etal.Variantsofchemokinereceptor2and
interleukin4receptor,butnotinterleukin10orFasligand,increaseriskofcervicalcancer.IntJCancer.2007121:24517.
[PubMed:17688234]
178.ZornigM,HueberA,BaumW,EvanG.Apoptosisregulatorsandtheirroleintumorigenesis.BiochimBiophysActa.
20011551:F137.[PubMed:11591448]
179.AndoK,HiroishiK,KanekoT,MoriyamaT,MutoY,KayagakiN,etal.Perforin,Fas/Fasligand,andTNFalphapathwaysas
specificandbystanderkillingmechanismsofhepatitisCvirusspecifichumanCTL.JImmunol.1997158:528391.[PubMed:9164947]
180.HuangQR,MorrisD,ManoliosN.IdentificationandcharacterizationofpolymorphismsinthepromoterregionofthehumanApo
1/Fas(CD95)gene.MolImmunol.199734:57782.[PubMed:9393960]
181.SibleyK,RollinsonS,AllanJM,SmithAG,LawGR,RoddamPL,etal.FunctionalFASpromoterpolymorphismsareassociated
withincreasedriskofacutemyeloidleukemia.CancerRes.200363:432730.[PubMed:12907599]

182.KanemitsuS,IharaK,SaifddinA,OtsukaT,TakeuchiT,NagayamaJ,etal.Afunctionalpolymorphisminfas(CD95/APO1)
genepromoterassociatedwithsystemiclupuserythematosus.JRheumatol.200229:11838.[PubMed:12064832]
183.LaiHC,LinWY,LinYW,ChangCC,YuMH,ChenCC,etal.GeneticpolymorphismsofFASandFASL(CD95/CD95L)genes
incervicalcarcinogenesis:Ananalysisofhaplotypeandgenegeneinteraction.GynecolOncol.200599:1138.[PubMed:15996722]
184.LaiHC,SytwuHK,SunCA,YuMH,YuCP,LiuHS,etal.SinglenucleotidepolymorphismatFaspromoterisassociatedwith
cervicalcarcinogenesis.IntJCancer.2003103:2215.[PubMed:12455036]
185.ChatterjeeK,EngelmarkM,GyllenstenU,DandaraC,vanderMerweL,GalalU,etal.FasandFasLgenepolymorphismsarenot
associatedwithcervicalcancerbutdifferamongBlackandMixedancestrySouthAfricans.BMCResNotes.20092:238.
[PMCID:PMC2787520][PubMed:19941645]
186.WuJ,MetzC,XuX,AbeR,GibsonAW,EdbergJC,etal.AnovelpolymorphicCAAT/enhancerbindingproteinbetaelementin
theFasLgenepromoteraltersFasligandexpression:AcandidatebackgroundgeneinAfricanAmericansystemiclupuserythematosus
patients.JImmunol.2003170:1328.[PubMed:12496392]
187.DybikowskaA,SliwinskiW,EmerichJ,PodhajskaAJ.EvaluationofFasgenepromoterpolymorphismincervicalcancerpatients.
IntJMolMed.200414:4758.[PubMed:15289903]
188.EngelmarkMT,RenkemaKY,GyllenstenUB.NoevidenceoftheinvolvementoftheFas670promoterpolymorphismincervical
cancerinsitu.IntJCancer.2004112:10845.[PubMed:15316939]
189.SergentanisTN,EconomopoulosKP.AssociationoftwoCASP8polymorphismswithbreastcancerrisk:Ametaanalysis.Breast
CancerResTreat.2010120:22934.[PubMed:19629679]
190.SunT,GaoY,TanW,MaS,ShiY,YaoJ,etal.AsixnucleotideinsertiondeletionpolymorphismintheCASP8promoteris
associatedwithsusceptibilitytomultiplecancers.NatGenet.200739:60513.[PubMed:17450141]
191.SunT,ZhouY,LiH,HanX,ShiY,WangL,etal.FASL844CpolymorphismisassociatedwithincreasedactivationinducedT
celldeathandriskofcervicalcancer.JExpMed.2005202:96774.[PMCID:PMC2213165][PubMed:16186185]
192.PlummerM,HerreroR,FranceschiS,MeijerCJ,SnijdersP,BoschFX,etal.Smokingandcervicalcancer:Pooledanalysisofthe
IARCmulticentriccasecontrolstudy.CancerCausesControl.200314:80514.[PubMed:14682438]
193.GoodmanMT,McDuffieK,HernandezB,BertramCC,WilkensLR,GuoC,etal.CYP1A1,GSTM1,andGSTT1

polymorphismsandtheriskofcervicalsquamousintraepitheliallesionsinamultiethnicpopulation.GynecolOncol.200181:2639.
[PubMed:11330960]
194.JuarezCedilloT,VallejoM,FragosoJM,HernandezHernandezDM,RodriguezPerezJM,SanchezGarciaS,etal.Theriskof
developingcervicalcancerinMexicanwomenisassociatedtoCYP1A1MspIpolymorphism.EurJCancer.200743:15905.
[PubMed:17512722]
195.JosephT,ChackoP,WesleyR,JayaprakashPG,JamesFV,PillaiMR.GermlinegeneticpolymorphismsofCYP1A1,GSTM1and
GSTT1genesinIndiancervicalcancer:Associationswithtumorprogression,ageandhumanpapillomavirusinfection.GynecolOncol.
2006101:4117.[PubMed:16360200]
196.TaskiranC,AktasD,YigitCelikN,AlikasifogluM,YuceK,TuncbilekE,etal.CYP1A1genepolymorphismasariskfactorfor
cervicalintraepithelialneoplasiaandinvasivecervicalcancer.GynecolOncol.2006101:5036.[PubMed:16403567]
197.ChenC,MadeleineMM,WeissNS,DalingJR.GlutathioneStransferaseM1genotypesandtheriskofsquamouscarcinomaofthe
cervix:Apopulationbasedcasecontrolstudy.AmJEpidemiol.1999150:56872.[PubMed:10489995]
198.SharmaA,SharmaJK,MurthyNS,MitraAB.PolymorphismsatGSTM1andGSTT1genelociandsusceptibilitytocervical
cancerinIndianpopulation.Neoplasma.200451:126.[PubMed:15004652]
199.IdleJR,ArmstrongM,BoddyAV,BousteadC,CholertonS,CooperJ,etal.Thepharmacogeneticsofchemicalcarcinogenesis.
Pharmacogenetics.19922:24658.[PubMed:1306125]
200.WorrallSF,CorriganM,HighA,StarrD,MatthiasC,WolfCR,etal.Susceptibilityandoutcomeinoralcancer:Preliminarydata
showinganassociationwithpolymorphismincytochromeP450CYP2D6.Pharmacogenetics.19988:4339.[PubMed:9825835]
201.WarwickA,SarhanisP,RedmanC,PembleS,TaylorJB,KettererB,etal.ThetaclassglutathioneStransferaseGSTT1genotypes
andsusceptibilitytocervicalneoplasia:InteractionswithGSTM1,CYP2D6andsmoking.Carcinogenesis.199415:28415.
[PubMed:8001244]
202.SobtiRC,KaurS,KaurP,SinghJ,GuptaI,JainV,etal.InteractionofpassivesmokingwithGST(GSTM1,GSTT1,andGSTP1)
genotypesintheriskofcervicalcancerinIndia.CancerGenetCytogenet.2006166:11723.[PubMed:16631467]
203.HayesJD,PulfordDJ.TheglutathioneStransferasesupergenefamily:RegulationofGSTandthecontributionoftheisoenzymes
tocancerchemoprotectionanddrugresistance.CritRevBiochemMolBiol.199530:445600.[PubMed:8770536]

204.UedaM,HungYC,TeraiY,SaitoJ,NunobikiO,NodaS,etal.GlutathioneStransferaseandp53polymorphismsincervical
carcinogenesis.GynecolOncol.200596:73640.[PubMed:15721419]
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