Imputation and subset-based association analysis across different cancer types identifies multiple

18 Pages·2014·0.62 MB·English

HumanMolecularGenetics,2014,Vol.23,No.24 6616–6633
doi:10.1093/hmg/ddu363
AdvanceAccesspublishedonJuly15,2014
Imputation and subset-based association analysis
across different cancer types identifies multiple
independent risk loci in the TERT-CLPTM1L region
on chromosome 5p15.33
ZhaomingWang1,5,BinZhu1,MingfengZhang1,HemangParikh1,JinpingJia1,CharlesC.
Chung1,5,JoshuaN.Sampson1,JasonW.Hoskins1,AmyHutchinson1,5,LaurieBurdette1,5,
AbdisamadIbrahim1,ChristopherHautman1,5,PreethiS.Raj1,ChristianC.Abnet1,AndrewA.
Adjei6,7,AndersAhlbom8,DemetriusAlbanes1,NaomiE.Allen11,ChristineB.Ambrosone12, Do
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XuChe58,Chien-JenChen60,61,Chih-YiChen62,Chung-HsingChen55,ConstanceChen63,Kuan-Yu t U
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Clavel-Chapelon73,GrahamA.Colditz74,JoanneS.Colt1,DavidConti30,MichaelB.Cook1,Victoria ity
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EricJ.Duell87,JoanneW.Elena88,Jin-HuFan89,HeatherSpencerFeigelson90,MariaFeychting8, ton
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JonineD.Figueroa1,AdrienneM.Flanagan91,92,JosephF.FraumeniJr1,NealD.Freedman1, n N
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Yu-TangGao101,SusanM.Gapstur86,MontserratGarcia-Closas1,102,ReinaGarcia-Closas103,Julie er 2
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Giles107,ElizabethM.Gillanders108,EdwardL.Giovannucci63,64,MichaelGoggins110,111,112,Nalan 4
Gokgoz100,AlisaM.Goldstein1,CarlosGonzalez113,RichardGorlick114,MarkH.Greene1,Myron
Gross115,H.BartonGrossman80,RobertGrubbIII116,JianGu81,PengGuan117,ChristopherA.
Haiman31,GoranHallmans19,SusanE.Hankinson95,CurtisC.Harris109,PatriciaHartge1,Claudia
Hattinger118,RichardB.Hayes1,119,120,QinchengHe117,LeeHelman3,BrianE.Henderson31,
∗Towhomcorrespondenceshouldbeaddressedat:LaboratoryofTranslationalGenomics,DivisionofCancerEpidemiologyandGenetics,NationalCancer
Institute,AdvancedTechnologyCenter,8717GrovemontCircle,Bethesda,MD20892-4605,USA.Email:[email protected]
†Present address: Center for Pediatrics and Adolescent Medicine, Department of Pediatric Hematology and Oncology, Hannover Medical School,
Hannover,Germany
PublishedbyOxfordUniversityPress2014.Thisworkiswrittenby(a)USGovernmentemployee(s)andisinthepublicdomaininthe
US.
HumanMolecularGenetics,2014,Vol.23,No.24 6617
RogerHenriksson18,JudithHoffman-Bolton121,ChancellorHohensee122,ElizabethA.Holly40,
Yun-ChulHong123,124,RobertN.Hoover1,H.DeanHosgoodIII126,Chin-FuHsiao56,57,AnnW.
Hsing72,127,ChaoAgnesHsiung56,NanHu1,WeiHu1,ZhibinHu128,Ming-ShyanHuang66,DavidJ.
Hunter63,77,78,129,PeterD.Inskip1,HidemiIto130,EricJ.Jacobs86,KevinB.Jacobs4,5,131,Mazda
Jenab41,Bu-TianJi1,ChristofferJohansen132,133,MattiasJohansson41,20,AlisonJohnson134,
RudolfKaaks50,AshishM.Kamat80,ArunaKamineni135,MargaretKaragas17,ChandKhanna3,
Kay-TeeKhaw137,ChristopherKim1,In-SamKim138,139,JinHeeKim123,YeulHongKim140,141,142,
Young-ChulKim143,YoungTaeKim125,ChangHyunKang125,YooJinJung125,CariM.Kitahara1,
AlisonP.Klein110,111,112,144,RobertKlein145,ManolisKogevinas147,148,149,150,Woon-PuayKoh151,68,
TakashiKohno152,LaurenceN.Kolonel153,CharlesKooperberg122,ChristianP.Kratz1,{,Vittorio
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EvelynTay6,7,PhilipR.Taylor1,YaoTettey6,7,DavidM.Thomas201,RobertoTirabosco92,Anne
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RebeccaTroisi1,AnnTruelove42,Ying-HuangTsai203,MargaretA.Tucker1,RosarioTumino204,
DavidVanDenBerg31,StephenK.VanDenEeden205,RoelVermeulen206,PaoloVineis207,208,Kala
Visvanathan121,UllaVogel209,210,ChaoyuWang1,ChengfengWang58,JunwenWang1,5,211,Sophia
S.Wang214,ElisabeteWeiderpass215,216,9,217,StephanieJ.Weinstein1,NicolasWentzensen1,
WilliamWheeler106,EmilyWhite122,JohnK.Wiencke218,AlicjaWolk10,BrianM.Wolpin94,95,Maria
PikWong212,MargaretWrensch218,ChenWu59,TangchunWu171,XifengWu81,Yi-LongWu219,JayS.
Wunder23,Yong-BingXiang101,JunXu213,HannahP.Yang1,Pan-ChyrYang66,YasushiYatabe220,
6618 HumanMolecularGenetics,2014,Vol.23,No.24
YuanqingYe81,EdwardD.Yeboah6,7,ZhihuaYin117,ChenYing68,Chong-JenYu199,KaiYu1,
Jian-MinYuan221,KristaA.Zanetti88,AnneZeleniuch-Jacquotte27,28,WeiZheng13,14,Baosen
Zhou117,LisaMirabello1,SharonA.Savage1,PeterKraft63,65,StephenJ.Chanock1,5,Meredith
Yeager1,5,MariaTereseLandi1,JianxinShi1,NilanjanChatterjee1andLaufeyT.Amundadottir1,∗
1DivisionofCancerEpidemiologyandGenetics,2DivisionofCancerPrevention,3CenterforCancerResearchand4Office
ofCancerGenomics,DepartmentofHealthandHumanServices,NationalCancerInstitute,NationalInstitutesofHealth,
Bethesda,MD,USA,5CancerGenomicsResearchLaboratory,NationalCancerInstitute,DivisionofCancer
EpidemiologyandGenetics,SAIC-Frederick,Inc.,FrederickNationalLaboratoryforCancerResearch,Frederick,MD,
USA,6KorleBuTeachingHospital,POBOX77,Accra,Ghana,7UniversityofGhanaMedicalSchool,POBox4236,Accra,
Ghana,8UnitofEpidemiology,InstituteofEnvironmentalMedicine,9DepartmentofMedicalEpidemiologyand
Biostatisticsand10UnitofNutritionalEpidemiology,InstituteofEnvironmentalMedicine,KarolinskaInstitutet,Stockholm,
D
Sweden,11ClinicalTrialServiceUnitandEpidemiologicalStudiesUnit,UniversityofOxford,Oxford,UK,12Departmentof o
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CancerPreventionandControl,RoswellParkCancerInstitute,Buffalo,NY,USA,13DivisionofEpidemiology,Department nlo
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ofMedicine,VanderbiltEpidemiologyCenter,14Vanderbilt-IngramCancerCenter,VanderbiltUniversitySchoolof de
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Medicine,Nashville,TN,USA,15PublicHealthDivisionofGipuzkoa,BasqueRegionalHealthDepartment,San fro
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Sebastian,Spain,16CIBERESP,CIBEREpidemiologiaySaludPublica,Madrid,Spain,17GeiselSchoolofMedicineat h
DCalinrtimcaoluMthe,dHicainneo/vNeur,trNitiHon,UalSRAe,s1e8aDrecpha,r2t0mDeenptaortfmReandtiaotfioPnuSblcicieHneceaslt,hOanncdoClolignyic,a19lDMeepdaicritnmee,n2t1DofePpuabrtlmiceHnetaolfthSuarngdical ttp://hm
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andPerioperativeSciences,UrologyandAndrologyand22DepartmentofSurgicalandPerioperativeSciences/Surgery, .ox
Umea˚ University,Umea˚,Sweden,23DivisionofUrologicSurgery,WashingtonUniversitySchoolofMedicine,StLouis, ford
MO,USA,24LitwinCentreforCancerGenetics,SamuelLunenfeldResearchInstitute,MtSinaiHospital,Universityof jou
rn
Toronto,Toronto,ON,Canada,25DepartmentofMedicalandSurgicalSpecialties,RadiologicalSciencesandPublic als
Health,UniversityofBrescia,Italy,26DepartmentofObstetricsandGynecologyand27DepartmentofPopulationHealth, .org
NewYorkUniversitySchoolofMedicine,NewYork,NY,USA,28NewYorkUniversityCancerInstitute,NewYork,NY, at U/
USA,29DepartmentofEpidemiology,UniversityofWashington,Seattle,WA,USA,30DepartmentofPreventiveMedicine, niv
BiostatisticsDivision,KeckSchoolofMedicineand31DepartmentofPreventiveMedicine,KeckSchoolofMedicine, ers
UniversityofSouthernCalifornia,LosAngeles,CA,USA,32DivisionofEnvironmentalHealthSciences,YaleSchoolof ity o
PublicHealth,NewHaven,Connecticut,USA,33DepartmentofClinicalSciencesandCommunityHealth,Universityof f W
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Milan,34DepartmentofPreventiveMedicine,FondazioneIRCCSCa’GrandaPoliclinicoHospital,Milan,Italy, sh
in
35InternationalEpidemiologyInstitute,Rockville,MD,USA,36DepartmentofEpidemiology,GermanInstituteofHuman gto
n
Nutrition,Potsdam-Rehbruecke,Germany,37InstituteforTranslationalEpidemiology,HematologyandMedical o
n
Oncology,MountSinaiHospitalSchoolofMedicine,NewYork,NY,USA,38DepartmentofOncology,Universityof N
o
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Cambridge,CambridgeCB22RE,UK,39InstitutNationaldelaSanteetdelaRechercheMedicale(INSERM)andInstitut em
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GustaveRoussy,Villejuif,France,40DepartmentofEpidemiologyandBiostatistics,UniversityofCalifornia er 2
SanFrancisco,SanFrancisco,CA,USA,41InternationalAgencyforResearchonCancer(IARC-WHO),Lyon,France, 1, 2
42Westat,Rockville,MD,USA,43NationalInstituteforPublicHealthandtheEnvironment(RIVM),Bilthoven,The 01
4
Netherlands,44DepartmentofGastroenterologyandHepatology,UniversityMedicalCentreUtrecht,Utrecht,The
Netherlands,45DivisionofPreventiveMedicine,BrighamandWomen’sHospital,Boston,MA,USA,46CentersforDisease
ControlandPrevention,NationalInstituteforOccupationalSafetyandHealth,Cincinnati,OH,USA,47CeRePP,Paris,
France,48AP-HP,DepartmentofUrology,TenonHospital,GHU-Est,Paris,France,49UPMCUnivParis06,GRCn85,
ONCOTYPE-URO,Paris,France,50GenomicEpidemiologyGroup,GermanCancerResearchCenter(DKFZ),
Heidelberg,Germany,51DepartmentofEpidemiology,SecondMilitaryMedicalUniversity,Shanghai,China,52Medical
OncologyDepartment,HospitalRamo´nyCajal,Madrid,Spain,53FacultyofMedicine,SchoolofMedicine,National
Yang-MingUniversity,Taipei,Taiwan,54DivisionofChestMedicine,DepartmentofInternalMedicine,TaichungVeterans
GeneralHospital,Taichung,Taiwan,55NationalInstituteofCancerResearch,56DivisionofBiostatisticsand
Bioinformatics,InstituteofPopulationHealthSciencesand57TaiwanLungCancerTissue/SpecimenInformation
ResourceCenter,NationalHealthResearchInstitutes,Zhunan,Taiwan,58DepartmentofAbdominalSurgeryand59State
KeyLaboratoryofMolecularOncology,CancerInstituteandHospital,ChineseAcademyofMedicalSciencesandPeking
UnionMedicalCollege,Beijing,China,60GenomicsResearchCenter,AcademiaSinica,Taipei,Taiwan,61Graduate
HumanMolecularGenetics,2014,Vol.23,No.24 6619
InstituteofEpidemiology,CollegeofPublicHealth,NationalTaiwanUniversity,Taipei,Taiwan,62CancerCenter,China
MedicalUniversityHospital,Taipei,Taiwan,63PrograminMolecularandGeneticEpidemiology,64DepartmentofNutrition
and65DepartmentofEpidemiology,HarvardSchoolofPublicHealth,Boston,MA,USA,66DepartmentofInternal
Medicine,NationalTaiwanUniversityHospitalandNationalTaiwanUniversityCollegeofMedicine,Taipei,Taiwan,
67DepartmentofEpidemiologyandPublicHealth,YongLooLinSchoolofMedicineand68SawSweeHockSchoolof
PublicHealth,NationalUniversityofSingapore,Singapore,69ChestDepartment,TaipeiVeteransGeneralHospital,
Taipei,Taiwan,70CollegeofMedicalScienceandTechnology,TaipeiMedicalUniversity,Taiwan,71SchoolofPublic
Health,UniversityofCalifornia,Berkeley,CA,USA,72CancerPreventionInstituteofCalifornia,Fremont,CA,USA,
73Inserm,CentreforResearchinEpidemiologyandPopulationHealth(CESP),Villejuif,France,74WashingtonUniversity
SchoolofMedicine,StLouis,MO,USA,75UrologicOncology,UniversityofColorado,Aurora,CO,USA,76Departmentof
PublicHealthSciences,SchoolofPublicHealth,UniversityofAlberta,Edmonton,AB,CanadaT6G2R3,77Departmentof
Medicine,ChanningDivisionofNetworkMedicineand78BrighamandWomen’sHospitalandHarvardMedicalSchool,
Boston,MA,USA,79ShanxiCancerHospital,Taiyuan,Shanxi,People’sRepublicofChina,80DepartmentofUrology,
D
81DepartmentofEpidemiology,82DepartmentofGastrointestinalMedicalOncology,83DepartmentofHealthDisparities ow
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Research,DivisionofOVP,CancerPreventionandPopulationSciences,andCenterforCommunity-Engaged lo
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TranslationalResearch,DuncanFamilyInstituteand84DepartmentofEpidemiology,DivisionofCancerPreventionand ed
PopulationSciences,TheUniversityofTexasMDAndersonCancerCenter,Houston,TX,USA,85ServicedeNeurologie fro
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Mazarin,GHPitie-Salpetriere,APHP,andUMR975INSERM-UPMC,CRICM,Paris,France,86EpidemiologyResearch http
Program,AmericanCancerSociety,Atlanta,GA,USA,87UnitofNutrition,EnvironmentandCancer,Cancer ://h
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EpidemiologyResearchProgram,BellvitgeBiomedicalResearchInstitute,CatalanInstituteofOncology(ICO-IDIBELL), g
Barcelona,Spain,88EpidemiologyandGenomicsResearchProgram,DivisionofCancerControlandPopulation .ox
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Sciences,Bethesda,MD,USA,89ShanghaiCancerInstitute,Shanghai,People’sRepublicofChina,90InstituteforHealth rd
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Research,KaiserPermanente,Denver,CO,USA,91UCLCancerInstitute,HuntleyStreet,LondonWC1E6BT,UK, urn
a
92RoyalNationalOrthopaedicHospitalNHSTrust,Stanmore,MiddlesexHA74LP,UK,93DepartmentofBiostatistics, ls
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UniversityofKansasMedicalCenter,KansasCity,KS,USA,94DepartmentofMedicalOncology,Dana-FarberCancer arg/
Institute,Boston,MA,USA,95ChanningLaboratory,DepartmentofMedicine,96DivisionofPreventiveMedicine, t U
n
DepartmentofMedicineand97DivisionofAging,DepartmentofMedicine,BrighamandWomen’sHospitalandHarvard iv
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MedicalSchool,Boston,MA,USA,98GenomicMedicineGroup,GalicianFoundationofGenomicMedicine,Complejo rsity
HospitalarioUniversitariodeSantiago,ServicioGalegodeSaude(SERGAS),InstitutodeInvestigacio´nSanitariade of W
Santiago(IDIS),SantiagodeCompostela,Spain,99SamuelLunenfeldResearchInstituteand100Lunenfeld-Tanenbaum a
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ResearchInstitute,MountSinaiHospital,Toronto,ON,Canada,101DepartmentofEpidemiology,ShanghaiCancer hin
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Institute,RenjiHospital,ShanghaiJiaotaongUniversitySchoolofMedicine,Shanghai,China,102DivisionofGeneticsand to
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Epidemiology,InstituteofCancerResearch,Sutton,UK,103UnidaddeInvestigacio´n,HospitalUniversitariodeCanarias, on
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LaLaguna,Spain,104NationwideChildren’sHospital,andTheOhioStateUniversityDepartmentofPathologyand ov
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Pediatrics,Columbus,OH,USA,105MassachusettsVeteran’sEpidemiology,ResearchandInformationCenter,Geriatric m
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ResearchEducationandClinicalCenter,VeteransAffairsBostonHealthcareSystem,Boston,MA,USA,106Information r 2
1
ManagementServicesInc.,Calverton,MD,USA,107CancerEpidemiologyCentre,TheCancerCouncilVictoria&Centre , 2
0
1
forMolecular,Environmental,Genetic,andAnalyticEpidemiology,TheUniversityofMelbourne,Victoria,Australia, 4
108DivisionofCancerControlandPopulationSciencesand109LaboratoryofHumanCarcinogenesis,CenterforCancer
Research,NationalCancerInstitute,Bethesda,MD,USA,110DepartmentofOncology,111DepartmentofPathologyand
112DepartmentofMedicine,TheSolGoldmanPancreaticResearchCenter,TheJohnsHopkinsUniversitySchoolof
Medicine,Baltimore,MD,USA,113UnitofNutrition,EnvironmentandCancer,CancerEpidemiologyResearch
Programme,CatalanInstituteofOncology(ICO),Barcelona,Spain,114AlbertEinsteinCollegeofMedicine,The
Children’sHospitalatMontefiore,Bronx,NY,USA,115DepartmentofLaboratoryMedicineandPathology,Schoolof
Medicine,UniversityofMinnesota,Minneapolis,MN,USA,116DepartmentofUrology,WashingtonUniversitySchoolof
Medicine,StLouis,MO,USA,117DepartmentofEpidemiology,SchoolofPublicHealth,ChinaMedicalUniversity,
Shenyang,China,118LaboratoryofExperimentalOncology,OrthopaedicRizzoliInstitute,Bologna,Italy,119Department
ofPopulationHealth,NewYorkUniversityLangoneMedicalCenterand120DepartmentofEnvironmentalMedicine,
NewYorkUniversityLangoneMedicalCenter,NewYorkUniversityCancerInstitute,NewYork,NY,USA,121Johns
HopkinsBloombergSchoolofPublicHealth,Baltimore,MD,USA,122DivisionofPublicHealthSciences,FredHutchinson
CancerResearchCenter,Seattle,WA,USA,123InstituteofEnvironmentalMedicine,SeoulNationalUniversityMedical
6620 HumanMolecularGenetics,2014,Vol.23,No.24
ResearchCenter,Seoul,RepublicofKorea,124DepartmentofPreventiveMedicineand125CancerResearchInstitute,
SeoulNationalUniversityCollegeofMedicine,Seoul,RepublicofKorea,126DepartmentofEpidemiologyandPopulation
Health,AlbertEinsteinCollegeofMedicine,Bronx,NY,USA,127StanfordCancerInstitute,StanfordUniversity,Stanford,
CA,USA,128DepartmentofEpidemiologyandBiostatistics,CancerCenter,NanjingMedicalUniversity,Nanjing,China,
129BroadInstituteofHarvardandMIT,Cambridge,MA,USA,130DivisionofEpidemiologyandPrevention,AichiCancer
CenterResearchInstitute,Nagoya,Japan,131Bioinformed,LLC,Gaithersburg,MD,USA,132DepartmentofOncology,
FinsenCenter,Rigshospitalet,Copenhagen,Denmark,133UnitofSurvivorship,DanishCancerSocietyResearchCenter,
Copenhagen,Denmark,134VermontCancerRegistry,Burlington,VT,USA,135GroupHealthResearchInstitute,Seattle,
WA,USA,136DepartmentofThoracicandCardiovascularSurgery,SeoulStMary’sHospital,Seoul,SouthKorea,
137SchoolofClinicalMedicine,UniversityofCambridge,UK,138DepartmentofBiochemistryand139DepartmentofCell
Biology,SchoolofMedicine,KyungpookNationalUniversity,Daegu,RepublicofKorea,140GenomicResearchCenterfor
LungandBreast/OvarianCancers,KoreaUniversityAnamHospital,Seoul,RepublicofKorea,141DepartmentofInternal
MedicineandDivisionofBrainand142DivisionofOncology/Hematology,DepartmentofInternalMedicine,Korea
D
UniversityCollegeofMedicine,Seoul,RepublicofKorea,143LungandEsophagealCancerClinic,ChonnamNational ow
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UniversityHwasunHospital,Hwasun-eup,RepublicofKorea,144DepartmentofEpidemiology,JohnsHopkinsBloomberg lo
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SchoolofPublicHealth,Baltimore,MD,USA,145DepartmentofMedicineand146DepartmentofEpidemiologyand ed
Biostatistics,MemorialSloan-KetteringCancerCenter,NewYork,NY,USA,147CentreforResearchinEnvironmental fro
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Epidemiology(CREAL),Barcelona,Spain,148IMIM(HospitaldelMarMedicalResearchInstitute),Barcelona,Spain, h
149CIBEREpidemiolog´ıaySaludPu´blica(CIBERESP),Barcelona,Spain,150NationalSchoolofPublicHealth,Athens, ttp://h
Greece,151Duke-NUSGraduateMedicalSchool,Singapore,Singapore,152DivisionofGenomeBiology,NationalCancer m
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CenterResearchInstitute,Tokyo,Japan,153EpidemiologyProgram,UniversityofHawaiiCancerCenter,Honolulu,HI, .ox
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USA,154FondazioneIRCCSIstitutoNazionaledeiTumori,Milano,Italy,155DepartmentofRespiratoryMedicine,Mitsui rd
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MemorialHospital,Tokyo,Japan,156DepartmentofPediatricOncology,A.Y.AnkaraOncologyTrainingandResearch urn
Hospital,Yenimahalle-Ankara,Turkey,157CentreNationaldeGenotypage,IG/CEA,EvryCedex,France,158Centre als
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d’E´tudeduPolymorphismHumain(CEPH),Paris,France,159TexasChildren’sCancerandHematologyCenters,160Scott rg
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DepartmentofUrologyand161DanL.DuncanCenter,BaylorCollegeofMedicine,Houston,TX,USA,162Departmentof t U
Pediatrics,UniversityClinicofNavarra,UniversidaddeNavarra,Pamplona,Spain,163DepartmentofCancer niv
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EpidemiologyandPrevention,MariaSklodowska-CurieCancerCenterandInstituteofOncology,Warsaw,Poland, rsity
164HumanGeneticsDivision,GenomeInstituteofSingapore,Singapore,165SchoolofLifeSciences,AnhuiMedical o
University,Hefei,China,166MinistryofEducationKeyLaboratoryofContemporaryAnthropology,SchoolofLifeSciences, f Wa
s
FudanUniversity,Shanghai,China,167StateKeyLaboratoryofGeneticEngineering,SchoolofLifeSciences,Fudan hin
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University,Shanghai,China,168CentroNacionaldeInvestigacionesOncologicas,MelchorFerna´ndezAlmagro,3, to
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MadridE-28029,Spain,169NationalInstituteforHealthandWelfare,Helsinki,Finland,170LucilePackardChildren’s on
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Hospital,StanfordUniversity,PaloAlto,CA,USA,171DepartmentofCardiac,ThoracicandVascularSciences,University o
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ofPadova,Padua,Italy,172DepartmentofPreventiveMedicine,KyushuUniversityFacultyofMedicalScicence,Fukuoka, m
b
Japan,173DepartmentofHealthSciencesResearch,MayoClinic,Rochester,MN,USA,174KeyLaboratoryfor er 2
1
EnvironmentandHealth,SchoolofPublicHealth,TongjiMedicalCollege,HuazhongUniversityofSciencesand , 2
0
Technology,Wuhan,China,175DepartmentofEpidemiology,DivisionofBiologyandMedicine,BrownUniversity, 14
Providence,RI,USA,176HealthSciencesResearchInstitute,UniversityofWarwick,Coventry,UK,177ComplexTraits
GeneticsTeamand178DivisionofBreastCancerResearch,InstituteofCancerResearch,London,UK,179Dipartimentodi
MedicinaClinicaeChirurgia,FedericoIIUniversity,Naples,Italy,180LungCancerCenter,KyungpookNationalUniversity
MedicalCenter,Daegu,RepublicofKorea,181JuliusCenterforHealthSciencesandPrimaryCare,UniversityMedical
Center,Utrecht,Utrecht,TheNetherlands,182DepartmentofEpidemiologyandBiostatistics,SchoolofPublicHealth,
ImperialCollegeLondon,London,UK,183DepartmentofGenomicsofCommonDisease,SchoolofPublicHealth,Imperial
CollegeLondon,London,UK,184NoferInstituteofOccupationalMedicine,Lodz,Poland,185DepartmentofEpidemiology,
CancerInstitute(Hospital),ChineseAcademyofMedicalSciences,Beijing,People’sRepublicofChina,186YaleSchoolof
PublicHealth,NewHaven,CT,USA,187DepartmentofInternalMedicine,InhaUniversityCollegeofMedicine,Incheon,
Korea,188KarmanosCancerInstituteandDepartmentofOncologyand189KarmanosCancerInstituteandDepartmentof
FamilyMedicineandPublicHealthSciences,WayneStateUniversitySchoolofMedicine,Detroit,MI,USA,190Maine
CancerRegistry,Augusta,ME,USA,191CentreforResearchinOccupationalHealth,UniversitatPompeuFabra,
Barcelona,Spain,192CIBERofEpidemiologyandPublicHealth(CIBERESP),193DepartmentofBiostatistics,MD
HumanMolecularGenetics,2014,Vol.23,No.24 6621
AndersonCancerCenter,Houston,TX,USA,194NutritionalEpidemiologyUnit,FondazioneIRCCSIstitutoNazionaledei
Tumori,Milan,Italy,195DepartmentofSurgery,DivisionofCardiothoracicSurgery,QueenMaryHospital,HongKong,
China,196DepartmentofNeurosurgery,UniversityofBonnMedicalCenter,Bonn,Germany,197DepartmentofPathology,
TheUniversityofMelbourne,Melbourne,VIC,Australia,198UniversityofMinnesota,Minneapolis,MN,USA,
199DepartmentofInternalMedicine,NationalChengKungUniversityHospitalandCollegeofMedicine,Tainan,Taiwan,
200InstitutoUniversitariodeOncolog´ıa,UniversidaddeOviedo,Oviedo,Spain,201SirPeterMacCallumDepartmentof
Oncology,UniversityofMelbourne,StAndrew’sPlace,EastMelbourne,VIC,Australia,202DanishCancerSociety
ResearchCenter,Copenhagen,Denmark,203DepartmentofPulmonaryMedicine,ChangGungMemorialHospital,
Chiayi,Taiwan,204CancerRegistryAssociazioneIbleaRicercaEpidemiologica,OnlusandAspRagusa,RagusaItaly,
205KaiserPermanenteNorthernCalifornia,Oakland,CA,USA,206DivisionofEnvironmentalEpidemiology,Institutefor
RiskAssessmentSciences(IRAS),UtrechtUniversity,Utrecht,TheNetherlands,207ImperialCollege,London,UK,
208HumanGeneticsFoundation(HuGeF),TorinoItaly,209NationalResearchCentrefortheWorkingEnvironment,
Copenhagen,Denmark,210NationalFoodInstitute,TechnicalUniversityofDenmark,Soborg,Denmark,211Department
D
o
ofBiochemistryandCentreforGenomicSciences,LKSFacultyofMedicine,TheUniversityofHongKong,HongKong w
n
SAR,China,212DepartmentofPathologyand213SchoolofPublicHealth,LiKaShing(LKS)FacultyofMedicine,The lo
a
d
UniversityofHongKong,HongKong,China,214DivisionofCancerEtiology,DepartmentofPopulationSciences,Cityof ed
HopeandtheBeckmanResearchInstitute,Duarte,CA,USA,215DepartmentofCommunityMedicine,FacultyofHealth fro
m
Sciences,UniversityofTromsø,TheArcticUniversityofNorway,Tromsø,Norway,216DepartmentofResearch,Cancer http
RegistryofNorway,Oslo,Norway,217SamfundetFolkha¨lsan,Helsinki,Finland,218UniversityofCaliforniaSanFrancisco, ://h
SanFrancisco,CA,USA,219GuangdongLungCancerInstitute,MedicalResearchCenterandCancerCenterof mg
GuangdongGeneralHospital,GuangdongAcademyofMedicalSciences,Guangzhou,China,220DepartmentofPathology .ox
fo
andMolecularDiagnostics,AichiCancerCenterHospitaland221UniversityofPittsburghCancerInstitute,Pittsburgh,PA, rd
jo
USAand222DepartmentofEnvironmentalHealth,KoreaNationalOpenUniversity,Seoul,RepublicofKorea urn
a
ls
.o
ReceivedApril22,2014;RevisedJune30,2014;AcceptedJuly8,2014 rg
a/
t U
n
Genome-wideassociationstudies(GWAS)havemappedriskallelesforatleast10distinctcancerstoasmall ive
rs
regionof63000bponchromosome5p15.33.ThisregionharborstheTERTandCLPTM1Lgenes;theformer ity
o
encodesthecatalyticsubunitoftelomerasereversetranscriptaseandthelattermayplayaroleinapoptosis. f W
Toinvestigatefurtherthegeneticarchitectureofcommonsusceptibilityallelesinthisregion,weconducted a
s
h
anagnosticsubset-basedmeta-analysis(associationanalysisbasedonsubsets)acrosssixdistinctcancers in
g
in34248casesand45036controls.Basedonsequentialconditionalanalysis,weidentifiedasmanyassixin- to
n
dependentrisklocimarkedbycommonsingle-nucleotidepolymorphisms:fiveintheTERTgene(Region1: on
rs7726159,P52.10310239;Region3:rs2853677,P53.30310236andPConditional52.3631028;Region4: Nov
rs2736098,P53.87310212andPConditional55.1931026,Region5:rs13172201,P50.041andPConditional5 em
2.0431026;andRegion6:rs10069690,P57.49310215andP 55.3531027)andoneintheneighbor- be
ingCLPTM1Lgene(Region2:rs451360;P51.90310218andPConditional 57.06310216).Betweenthreeandfive r 21
Conditional , 2
cancersmappedtoeachindependentlocuswithbothrisk-enhancingandprotectiveeffects.Allele-specific 0
1
4
effectsonDNAmethylationwereseenforasubsetofriskloci,indicatingthatmethylationandsubsequent
effectsongeneexpressionmaycontributetothebiologyofriskvariantson5p15.33.Ourresultsprovide
strongsupportforextensivepleiotropyacrossthisregionof5p15.33,toanextentnotpreviouslyobservedin
othercancersusceptibilityloci.
susceptibilityallelessuggeststhattheregionharborsanimport-
INTRODUCTION
antsetofelementsthatcouldinfluencemultiplecancers.Ithas
Genome-wideassociationstudies(GWAS)haveidentifiedinde- beenobservedpreviouslythatoneallelemaybeprotectivefor
pendentsusceptibilitylociinaregiononchromosome5p15.33 one cancer while conferring susceptibility to another (15).
that are associated with at least 10 distinct cancers. The pub- These independent loci map to (cid:3)63,000 bp of 5p15.33 that
lished findings include bladder (1), estrogen-negative breast harbors two plausible candidate genes: TERT, which encodes
(2), glioma (3), lung (4–7), ovary (8), melanoma (9), non- the catalytic subunit of telomerase reverse transcriptase (16)
melanomaskin(10,11),pancreas(12),prostate(13)andtesticu- andCLPTM1L,whichencodesthecleftlipandpalate-associated
largermcellcancer(14).Thisdegreeofpleiotropyforcommon transmembrane 1 like protein (also called cisplatin resistance
6622 HumanMolecularGenetics,2014,Vol.23,No.24
related protein, CRR9). CLPTM1L appears to play a role in four SNPs, ranked by P-values, were highly correlated with
apoptosis and cytokinesis, is overexpressed in both lung and the index SNP based on 1000G CEU data: rs7725218 (P¼
pancreaticcancerandisrequiredforKRASdrivenlungcancer 2.98×10239, pair-wise r2¼0.90), rs4449583 (P¼3.37×
(17–21). Germline mutations in TERT can cause dyskeratosis 10239,pair-wiser2¼1.0),rs7705526(P¼1.00×10236,pair-
congenita(DC),acancer-proneinheritedbonemarrowfailure wise r2¼0.74) and rs4975538 (P¼4.11×10232, pair-wise
syndromecausedbyaberranttelomerebiology(22).Clinically r2¼0.76). These five SNPs reside in the second and third
related telomere biology disorders, including idiopathic pul- intronoftheTERTgeneandarecommon,witheffectallelefre-
monary fibrosis and acquired aplastic anemia, can also be quencies ranging between 0.18 and 0.43 in African (AFR),
causedbygermlineTERTmutations(reviewedin23). 0.35–0.37inAsian(ASN)and0.32–0.38inEuropean(EUR)
Toinvestigatethegeneticarchitectureofcommonsuscepti- populations,eachestimatedinthe1000Gproject(Supplemen-
bility alleles across this region of 5p15.33 in multiple cancer tary Material, Table S2). A search for surrogates using an r2
sites,weutilizedarecentlydevelopedmethodcalledassociation threshold of 0.7 across a 1Mb window centered on the index
analysis based on subsets (ASSET) that combines association SNP did not identify additional highly correlated SNPs. The
signals for an SNP across multiple traits by exploring subsets effect allele (A) of rs7726159 was positively associated with
ofstudiesfortrueassociationsignalsinthesame,ortheopposite glioma (Glioma Scan) and lung cancer (Asian Lung) (P¼
D
direction, while accounting for the multiple testing required 4.38×10236, OR ¼1.47; 95% CI¼1.38–1.56), but o
Combined w
(24). The method has been shown to be more powerful than negativelyassociatedwithtesticularcancer(TGCTNCI),pros- nlo
the standard meta-analysis in the presence of heterogeneity, tate cancer (Pegasus and AdvPrCa) and pancreatic cancer ad
e
wsuhbesreettohfetreafiftescotro/afnadsmpeacyifihcavSeNdPifmfeirgehnttbdeirreecsttiroicntseodftoasosonclyiaa- 0(C.8h0in–a0P.9C1))((PFi¼g.25A.0)7.×1026, ORCombined¼0.85; 95% CI¼ d from
tionsfordifferenttraits(24). ThemostsignificantSNPafterconditioningonrs7726159was h
rs451360(P¼1.90×10218;PConditional¼7.06×10216),res- ttp://h
idinginintron13ofCLPTM1LandmarkingRegion2(Fig.1, m
Table1).SixSNPswerecorrelatedwithrs451360withanr2. g.o
RESULTS x
0.7, all located within 500kb of this SNP and spanning the fo
Inthisstudy,weconductedacross-cancerfine-mappinganalysis entire length of CLPTM1L: rs380145, rs13170453, rs37004, rdjo
u
ofaregiononchromosome5p15.33knowntobeassociatedwith rs36115365, rs35953391 and rs7446461. This effect allele rn
a
multiple cancer sites. We imputed each dataset across a 2Mb (rs451360-A)waspositivelyassociatedwithpancreatic cancer ls
window (chr5: 250000–2250000; hg19) using the 1000 (PanScan) and testicular cancer (TGCT NCI) (P¼4.38× .org
Genomes (1000G) and DCEG reference datasets (25,26) and 10213,OR ¼1.34;95%CI¼1.24–1.45),butnegative- a/
Combined t U
appliedasubset-basedmeta-analysismethod(ASSET)(24)to lyassociatedwithlungcancer(AALung,AsianLungandEur n
caonmdbMineethroedsusltfsoarcdroestasislsix).cTahnicserms e(1th1osdtuhdaiess)be(seenesMhoawtenriatlos L0.u9n0g))((FPig¼. 29B.5)0. ×Alt1h0o2u8g,hOlRaCrgoembdiniefdfe¼ren0c.8e5s;w95e%reCseIe¼n 0in.8t0h–e iversity
improve power and interpretation when compared with other effect allele frequencies across the 1000G continental popula- o
traditionalmethodsfortheanalysisofheterogeneoustraits(24). tions, 0.02–0.03 in AFR, 0.12 in ASN and 0.17–0.24 in EUR f W
a
Inthefirstanalysis,wefocusedonsixdistinctcancersitesin (Supplementary Material, Table S2), the signal was still suffi- sh
in
which5p15.33hadpreviouslybeenreportedandhadanominal cientlystrongtobedetected,particularlyinAfricanandAsian g
to
P-valueinourdataset(‘Tier-Istudies’scans,seeMaterialsand lungstudies,suggestingitsimportanceinlungcanceretiology. n o
Methods). We performed the analysis across all studies (77% Inoursequential conditionalanalysis,rs2853677(locatedin n N
European, 7% African American and 16% Asian ancestry, thefirstintronofTERT)wasthemostsignificantSNPaftercon- ov
e
ALLscans),and, because themajorityof studies andsubjects ditioningonbothrs7726159andrs451360,thusmarkingRegion m
b
wtheisregorofuEpuoronplyea(nEUanRcessctrayn,s)w.eBcoonnfedrurcotneidcpoarrraelclteilonanwalaysseusseidn 3Tab(lPe¼1).3.N30o×ad1d0it2io3n6;al PSNCoPndsitwioniathl¼an2.r326.×01.072w8)ere(Floigc.ate1d, er 21
toassesssignificance,usingthethresholdat1.3×1025,based within 500kb of this SNP, which has relatively low LD with , 20
1
onthenumberofsingle-nucleotidepolymorphisms(SNPs)ana- both rs7726159 (r2¼0.13) and rs451360 (r2¼0.12) in 4
lyzed across the region (n¼1924) and the two analyses per- 1000GCEUdata.Region3(rs2853677-A)waspositivelyasso-
formed (ALL or EUR scans) (see Materials and Methods). In ciatedwithtesticularcancer(TGCTNCI)andpancreaticcancer
thesecondanalysis,weexaminedtheregionsidentifiedabove (PanScanandChinaPC)(P¼1.36×1027,OR ¼1.22;
Combined
ineightcancersinwhich5p15.33hadnotbeenreportedinthe 95% CI¼1.13–1.31), but negatively associated with lung
literature(NHGRICatalogofPublishedGWASstudies:http:// cancer (Asian Lung and AA Lung) and glioma (Glioma scan)
www.genome.gov/gwastudies/), or did not show a nominal (P¼2.79×10231,OR ¼0.73;95%CI¼0.70–0.77)
Combined
P-valueinourdataset(‘Tier-IIstudies’). (Fig.2C).Theeffectallelefrequencyforrs2853677wasconsist-
Application of ASSET by sequential conditioning of asso- entacrossthethreecontinental1000Gpopulationscorrespond-
ciated SNPs revealed up to six independent loci on 5p15.33, ingtothestudiesincludedinthisanalysis:0.60inEUR,0.67in
eachinfluencingriskofmultiplecancers(Fig.1,Table1;Sup- ASNand0.71inAFR(SupplementaryMaterial,TableS2).
plementary Material, Table S1). In the primary analysis of all A conditional analysis based on the three SNPs above
subjects,weperformedtheASSETmeta-analysisbasedonun- (rs7726159, rs451360 and rs2853677) yielded Region 4,
conditional association results from each of the six cancer marked by rs2736098 (P¼3.87×10212; P ¼
Conditional
scans (11 studies). This identified rs7726159 with the lowest 5.19×1026), a synonymous variant (A305A) in the second
P-value(P¼2.10×10239),thusmarkingRegion1.Thenext exonofTERT(Fig.1,Table1).ThreeadditionalSNPswithan
HumanMolecularGenetics,2014,Vol.23,No.24 6623
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Figure1.SequentialconditionalanalysesandASSETmeta-analysesidentifieduptosixindependentsignalsfortheTERT-CLPTM1Lregiononchromosome5p15.33.
SNPsmarkingeachregionareplottedintheupperpanelwithtwoP-values(soliddiamondscorrespondtoanunconditionaltestandopendiamondscorrespondtoa
conditionaltest)onanegativelogscale(lefty-axis)againstgenomiccoordinates(x-axis,hg19).CancersfromdifferentGWASscans(acronymsdetailedinboxintop
panel)thatareassociatedwithineachregioninthesubsetmeta-analysisarelisted(red,positivelyassociated;green,negativelyassociated)fromtheunconditional
ASSETmeta-analysis.EffectallelesareshownnexttoSNPidentifiers.Recombinationhotspots(curvedlines,toppanel)wereinferredfromthreepopulations
fromtheDCEGImputationReferenceSetversion1(red,CEU;green,ASN;blue,YRI)asthelikelihoodratiostatistics(righty-axis).Alsoshownarethegenestruc-
turesforTERT,MIR4457andCLPTM1L(middlepanel),andLDheatmapbasedonr2usingthe1000GenomesCEUpopulation(lowerpanel).Resultsareshownfor
theALLanalysisexcepttheregionmarkedbyrs10069690(toppanel)andlabeledwitha‘∗’thatwasidentifiedintheEuropeanancestry-onlyanalysis(EUR).
6
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Table1. AssociationresultsforSNPsonchromosome5p15.33withtheriskofcancer
G
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SNP Gene Region Position UPonsciotinvdeiltyionalOR(95N%egCatIi)vely UP-nvcaolnudeitional SPiogsnitiifivcealyntphenotypeclusters Negatively CPoosnidtiivtieolynalOR(95%NCeI)gatively CP-ovnadliuteional etic
s
associated associated associated associated associated associated ,
2
0
ALL 1
4
rs7726159 TERT 1 1282319 1.47(1.38–1.56) 0.85(0.80–0.91) 2.10×10239 AsianLung,GliomaScan TGCTNCI,Pegasus, ,
V
AdvPrCa,ChinaPC
o
rs451360 CLPTM1L 2 1319680 1.34(1.24–1.45) 0.85(0.80–0.90) 1.90×10218 PanScan,TGCTNCI EurLung,AfrAmLung, 1.33(1.23–1.44) 0.86(0.81–0.92) 7.06×10216 l.
AsianLung 2
rs2853677 TERT 3 1287194 1.22(1.13–1.31) 0.73(0.70–0.77) 3.30×10236 TGCTNCI,PanScan, AsianLunga, 1.11(0.94–1.30) 0.80(0.74–0.86) 2.36×1028 3,
ChinaPC GliomaScan, N
AfrAmLung o.
rs2736098 TERT 4 1294086 1.15(1.10–1.21) 0.81(0.74–0.89) 3.87×10212 AfrAmLung,Pegasus, PanScan,TGCTNCIa 1.18(1.10–1.25) 0.94(0.67–1.31) 5.19×1026 2
EurLunga,BladderNCI 4
rs13172201 TERT 5 1271661 1.06(0.80–1.41) 0.84(0.73–0.96) 5.00×1022 EurLung,Pegasusa, TGCTNCI,GliomaScan 1.13(1.03–1.23) 0.81(0.70–0.92) 1.31×1024
PanScan,AfrAmLunga
EUR
rs4449583 TERT 1 1284135 1.50(1.35–1.68) 0.89(0.83–0.94) 1.02×10215 GliomaScan TGCTNCI,Pegasus,
AdvPrCa,PanScan
rs13170453 CLPTM1L 2 1317481 1.34(1.24–1.45) 0.87(0.80–0.95) 6.69×10215 PanScan,TGCTNCI EurLung 1.33(1.22–1.44) 0.86(0.80–0.93) 6.67×10214
rs10069690 TERT 6 1279790 1.48(1.31–1.67) 0.87(0.83–0.92) 7.49×10215 GliomaScana AdvPrCa,TGCTNCIa, NA 0.77(0.69–0.85) 5.35×1027
PanScana,Bladder
NCI,Pegasusa
rs13172201 TERT 5 1271661 1.07(0.88–1.29) 0.84(0.73–0.96) 4.08×1022 EurLung,Pegasusa, TGCTNCI,GliomaScan 1.13(1.04–1.22) 0.82(0.75–0.90) 2.04×1026
PanScan
rs2736098 TERT 4 1294086 1.14(1.08–1.20) 0.81(0.74–0.89) 5.73×10210 Pegasus,EurLunga,Bladder PanScan,TGCTNCI 1.23(1.11–1.35) 0.88(0.75–1.02) 6.31×1025
NCIa
Theresultsfromtheimputationandsubset-basedASSETmeta-analysisisshownforthe‘ALL’scansthatinclude11GWASscansperformedinsubjectsofEuropean,AsianandAfricanAmericanancestry;andforthe‘EUR’scansthatinclude
eightscansperformedinsubjectsofEuropeanancestry.ScanacronymsaredetailedinMaterialsandMethods.ListedareSNPsthatmarkeachoftheregionsidentified,gene,genomiclocation,unconditionalandconditionalP-valuesand
GWASscansthatwerepositivelyornegativelyassociatedwiththeminoralleleforeachSNP/region.NotethatdifferenthighlycorrelatedSNPsmaymarkthesameregioninthe‘ALL’vs.the‘EUR’analysis(Regions1and2).NAindicates
thatnoscanwasassociatedwithaparticularregion.
aCancersitesthatwerenolongersignificantintheconditionalanalysis.
4102 ,12 rebmevoN no notgnihsaW fo ytisrevinU ta /gro.slanruojdrofxo.gmh//:ptth morf dedaolnwoD
HumanMolecularGenetics,2014,Vol.23,No.24 6625
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Figure2.(A–F)Forestplotsforindividualrisklocionchr5p15.33fortheunconditionalASSETmeta-analysis.Foreachcancer/GWASscan,ORand95%CIwere
listedandplottedalongeachlineaspertheunconditionalassociationanalysis.AverticallineofOR¼1indicatesthenull.TwosummarylineslistORsfortheposi-
tivelyornegativelyassociatedsubsetsasestimatedbytheASSETprogram.(A)rs7726159,(B)rs451360,(C)rs2853677,(D)rs2736098,(E)rs13172201and(F)
rs10069690intheanalysisofEuropean-ancestrystudiesonly.ForestplotsfortheconditionalanalysesareshowninSupplementaryMaterial,FigureS1A–E.