6533b856fe1ef96bd12b1efb

RESEARCH PRODUCT

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Michael LushHans WildiersChristopher A. HaimanNils SchoofPer HallBeatrice MelinHiltrud BrauchHiltrud BrauchLiisa M. PelttariAngela Brooks-wilsonAngela Brooks-wilsonLaima TihomirovaIngo B. RunnebaumHui CaiKenneth OffitMichael P. LuxRobert EdwardsJulia A. KnightIgnace VergoteArto LeminenAlan AshworthKyriaki MichailidouMartha J. ShrubsoleSophie GiraudNadeem SiddiquiKatri PylkäsSune F. NielsenVernon S. PankratzLenka ForetovaAnna González-neiraIan TomlinsonThérèse TruongAnna Marie MulliganAndreas Du BoisChristi J. Van AsperenNuria ÁLvarezM. Pilar ZamoraTheo A. Mvan OsSusan J. RamusOlivia FletcherUsha MenonOlivier CaronDieter Flesch-janysSara H. OlsonEllen L. GoodeYael LaitmanJingmei LiLynne R. WilkensCarmel ApicellaBrooke L. FridleyRobert LubenMark S. GoldbergMary Anne RossingMary Anne RossingDominique Stoppa-lyonnetJonathan BeesleyJan LubinskiPeterlongo PaoloPhuong L. MaiHenrik FlygerThilo DörkDouglas A. LevineRob B. Van Der LuijtStig E. BojesenStig E. BojesenJavier BenitezNatalia BogdanovaStephen J. ChanockAndrew K. GodwinSharon E. JohnattyHelga B. SalvesenJuliet D. FrenchDaphne Gschwantler KaulichRod KarevanArif B. EkiciMarc FrenayTaru A. MuranenJirong LongCatherine S. HealeyCraig LuccariniChen-yang ShenChen-yang ShenLorna GibsonPascal GuénelHidemi ItoNicholas T. WoodsDrakoulis YannoukakosThomas HansenFrancesca DamiolaValérie BonadonaSatoyo HosonoMarion PiedmonteSteve EllisSuleeporn SangrajrangAleksandra Gentry-maharajJames MckayOlga M. SinilnikovaJennifer A. DohertyXiao-ou ShuCurtis OlswoldNhu D. LeMichael J. KerinMalcolm C. PikeMalcolm C. PikeJenny Chang-claudeGianluca SeveriGianluca SeveriMichael JonesLinda E. KelemenLoic Le MarchandMaureen E. HoatlinFredrick R. SchumacherDieter NiederacherMichael E. CarneyAngela CoxAttila TeomanHannah P. YangGraham G. GilesGraham G. GilesGraham G. GilesJianjun LiuXiaoqing ChenElisa V. BanderaTanja PejovicGalina LurieKaroline KuchenbaeckerMariusz BidzińskiChanel E. SmartMaartje J. HooningJose Ignacio Arias Perez Anne Marie GerdesL. RogmannEngel ChristophHarvey A. RischIgnacio BlancoIsabel Dos Santos SilvaHoda Anton-culverCamilla KrakstadVolker ArndtFoluso O. AdemuyiwaFrans B. L. HogervorstStacey L. EdwardsFlorian HeitzVeli-matti KosmaBeth Y. KarlanRobert A. VierkantIrene L. AndrulisAgnieszka Dansonka-mieszkowskaHanne Meijers-heijboerAlison M. DunningSabapathy P. BalasubramanianPenny SoucyEdwin S. IversenNevanlinna HeliCeleste Leigh PearceMelissa C. SoutheyHoward C. ShenKenneth MuirKenneth MuirJolanta LissowskaClareann H. BunkerJudy GarberDavid Van Den BergYin Ling WooBrigitte Bressac-de PailleretsRebecca HeinRebecca HeinArnold NorbertSaila KauppilaLisa WalkerCezary CybulskiEstrid HøgdallAnthony J. SwerdlowRobert WinqvistSusanne K. KjaerChrista StegmaierKazuo TajimaCaroline BaynesValerie GaborieauKeitaro MatsuoEd DicksIrene OrlowTorben A KruseRachel Palmieri WeberDavid E. GoldgarJakubowska AnnaHonglin SongAntonis C. AntoniouPaul D.p. PharoahKatja K.h. AbenLambertus A. KiemeneyLaurence FaivreStefan NickelsJoellen M. SchildkrautYu Tang GaoValerie McguireCharles L. ShapiroSebastian M. ArmasuKatherine L. NathansonMarjanka K. SchmidtSusan L. NeuhausenJolanta KupryjanczykJanet E. OlsonNicolas WentzensenDong Young NohMaya GhoussainiIan G. CampbellAnnegien BroeksGustavo C. RodriguezRebecca L. JohnstonShan Wang-gohrkeMonica BarileVesa KatajaMelanie MaranianShahana AhmedChristof SohnJulie M. CunninghamWeiva SiehShani Shimon PaluchRiccardo DolcettiJohn W.m. MartensManjeet K. BollaShelley S. TworogerRobert S. BrownAllan JensenHui MiaoBoris WinterhoffMari K. HalleArndt HartmannLoris BernardBrian E. HendersonEls WautersC. BlomqvistDaniel O. StramKaren A. PooleyRoberta B. NessJames PaulHilda A. PickettHilda A. PickettWei ZhengSandra Deming-halversonSoo Hwang TeoAndrew LeeThomas A. SellersPhilip IauD. Gareth EvansFrançis BacotSunil R. LakhaniSunil R. LakhaniQin WangNick OrrCeline M. VachonEdith OlahGong YangSvend Aage EngelholmMartine DumontLinda S. CookDaniel C. TessierEvgeny N. ImyanitovRadice PaoloMikael HartmanMikael HartmanAnnika LindblomJohn R. MclaughlinRadka PlatteJenny Permuth-weyKeun-young YooAndrew BerchuckRoger R. ReddelRoger R. ReddelM. John KennedyToru NakanishiAllison F. VitonisMelissa C. LarsonAnna H. WuHelmut DeisslerGiuseppe GianniniBarbara WappenschmidtTomasz ByrskiM. Kamran IkramNatalia AntonenkovaBanu ArunPeter HillemannsWilliam BlotSiti Zawiah OmarSue HealeyTrevor ColeCheng Har YipMatthias DürstMark E. RobsonRoger L. MilneTimothy R. RebbeckJaana M. HartikainenMieke KriegeC. Ellen Van Der SchootHansjoerg PlendlYasushi YatabeJan C. OosterwijkClaus HøgdallRob A. E. M. TollenaarJacek GronwaldYi LuKate LawrensonMichael D. StutzMichael D. StutzChia-ni HsiungAlvaro N.a. MonteiroMaren WeischerPhilipp HarterNicola MillerLisa B. SignorelloKatarzyna DurdaPeter LichtnerRitu SalaniAlfons MeindlMontserrat Garcia-closasGeorge FountzilasUffe Birk JensenThomas BrüningLaura BagliettoLaura BagliettoAnne M. Van AltenaKristine M. HillmanPeissel BernardTrinidad CaldésRosemarie DavidsonJulian BarwellPeter DevileeJenny LesterQiuyin CaiHeiko MüllerJyh Cherng YuKerstin RhiemMuy Kheng TeaSharon A. SavageÅKe BorgDaniel VincentAntoinette HollestelleKatarzyna JaworskaKatarzyna JaworskaMat Adenan Noor AzmiYon KoKimberly R. KalliDebra FrostMartin GoreChiu-chen Tseng Georgia Chenevix TrenchPornthep SiriwanarangsanEvelyn DespierreFergus J. CouchVijayalakshmi ShridharArtitaya LophatananonArtitaya LophatananonAmanda B. SpurdleJ. DennisUte HamannVessela N. KristensenFrederik MarméJonathan TyrerArja Jukkola-vuorinenWei LuPeter A. FaschingPeter A. FaschingBruno BuecherKristiina AittomäkiKirsten B. MoysichLesley McguffogMine S. CicekGuillermo PitaArjen R. MensenkampAgnes JagerCatherine M. PhelanJacques SimardMing-feng HouHiroji IwataJames M. FlanaganElena FinebergSusan M. DomchekCsilla SzaboDiether LambrechtsAnja RudolphDaehee KangGottfried E. KonecnyEitan FriedmanArgyrios ZiogasArto MannermaaSusan PeockMatti A. RookusChristian F. SingerClaire MulotSiranoush ManoukianJohanna RantalaHelen TsimiklisGord GlendonPierre Laurent-puigBarbara BrouwersFilomena FicarazziJonine D. Figueroa Anne Bine SkytteCaroline SeynaeveChristian SutterRita K. SchmutzlerJulian PetoJeffrey N. WeitzelKathryn L. TerryBørge G. NordestgaardSimon A. GaytherBarbara BurwinkelIra SchwaabSteven A. NarodElisabeth WikRalf BützowMontagna MarcoMark H. GreeneLinde M. BraafJanusz MenkiszakKamila CzeneSarah Stewart-brownKees E. P. Van RoozendaalAndreas SchneeweissBarrowdale DanielElinor J. SawyerAlice S. WhittemoreMarc T. GoodmanJudith E. BrownKunle OdunsiJohn L. HopperNina DitschLeon F.a.g. MassugerHermann BrennerJoaquin J. GarciaXianshu WangSusan L. SlagerAleksandra Tołoczko-grabarekSylvie MazoyerDiana EcclesYik Ying TeoIwona K. RzepeckaBernardo BonanniS. MargolinDaniela ZaffaroniYew Ching TehAns M Wvan Den OuwelandBent EjlertsenMaria SollerMitul ShahMatthias W. BeckmannElizabeth M. PooleJ. Margriet ColléeLorna Rodriguez-rodriguezSandrina LambrechtsDaniel W. CramerDouglas F. EastonVirginie Caux-moncoutierMads ThomassenKeith Humphreys

subject

TelomeraseMessengerCàncer d'ovariEstrogen receptorAetiology screening and detection [ONCOL 5]0302 clinical medicineBreast cancerRisk FactorsAlternative Splicing; Biomarkers Tumor; Breast Neoplasms; Case-Control Studies; Chromatin; DNA Methylation; Female; Gene Expression Profiling; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Luciferases; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Polymorphism Single Nucleotide; RNA Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Telomerase; Telomere; GeneticsGenotypeBUCCAL CELLSLuciferasesTelomeraseOligonucleotide Array Sequence AnalysisOvarian Neoplasms0303 health sciencesTumorTelòmerReverse Transcriptase Polymerase Chain ReactionGENETIC-VARIATIONCOMMON VARIANTSSingle Nucleotidetert-clptm1l locus; genome-wide association; genetic-variation; susceptibility loci; buccal cells; fibroblasts; common variants; carcinoma; reverse-transcriptase htert; metaanalysisTelomereAetiology screening and detection Immune Regulation [ONCOL 5]Chromatin3. Good healthTumor Markers Biological030220 oncology & carcinogenesisFemaleFIBROBLASTSGenotypeSUSCEPTIBILITY LOCICARCINOMASingle-nucleotide polymorphismBreast NeoplasmsBiologyReal-Time Polymerase Chain ReactionPolymorphism Single NucleotideArticleCàncer de mama03 medical and health sciencesBreast cancerSDG 3 - Good Health and Well-beingTranslational research [ONCOL 3]Ovarian cancermedicineGeneticsBiomarkers TumorHumansGenetic Predisposition to DiseaseRNA MessengerPolymorphismAlleleGENOME-WIDE ASSOCIATIONMETAANALYSIS030304 developmental biologyMolecular epidemiology Aetiology screening and detection [NCEBP 1]Breast cancer susceptibilityHereditary cancer and cancer-related syndromes [ONCOL 1]Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3]Gene Expression ProfilingDNA Methylationmedicine.diseaseMolecular biologyTERT-CLPTM1L LOCUSTelomereMinor allele frequencyAlternative SplicingGenetic LociCase-Control StudiesRNABiomarkersREVERSE-TRANSCRIPTASE HTERTGenome-Wide Association Study

description

Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed

yearjournalcountryeditionlanguage
2013-04-01Nature genetics
10.1038/ng.2566https://doi.org/10.1038/ng.2566