A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
Juliette CoignardMichael LushJonathan BeesleyTracy A O'MaraJoe G DennisJonathan P TyrerDaniel R BarnesLesley McGuffogGoska LeslieManjeet K BollaMuriel A AdankSimona AgataThomas U AhearnKristiina AittomäkiIrene L AndrulisHoda Anton-CulverVolker ArndtNorbert ArnoldKristan J AronsonBanu K ArunAnnelie AugustinssonJacopo AzzolliniDaniel BarrowdaleCaroline BaynesHeiko BecherMarina BermishevaLeslie BernsteinKatarzyna BiałkowskaCarl BlomqvistStig Egil BojesenBernardo BonanniAke BorgHiltrud B BrauchHermann BrennerBarbara BurwinkelSaundra S BuysTrinidad CaldésMaria A CaligoDaniele CampaBrian D CarterJose E CastelaoJenny Chang-ClaudeStephen J ChanockWendy K ChungKathleen B M ClaesChristine L Clarkenull nullnull nullJ Margriet ColléeDon M ConroyKamila CzeneMary B DalyPeter DevileeOrland DiezYuan Chun DingSusan M DomchekThilo DörkIsabel Dos-Santos-SilvaAlison M DunningMiriam V DwekDiana M EcclesA Heather EliassenChristoph EngelMikael ErikssonD Gareth EvansPeter A FaschingHenrik FlygerFlorentia FostiraEitan FriedmanGeza BenkeDebra FrostManuela Gago-DominguezSusan M GapsturJudy GarberVanesa Garcia-BarberanMontserrat Garcia-ClosasJosé Angel García-SaenzMia M GaudetSimon A GaytherAndrea GehrigVassilios GeorgouliasGraham G GilesAndrew K GodwinMark S GoldbergDavid E GoldgarAnna González-NeiraMark H GreenePascal GuénelLothar HaeberleEric HahnenChristopher A HaimanNiclas HåkanssonPer HallUte HamannPatricia A HarringtonSteven N HartWei HeFrans B L HogervorstAntoinette HollestelleJohn L HopperDarling J HorcasitasPeter J HulickDavid J HunterEvgeny N Imyanitovnull nullnull nullnull nullAgnes JagerAnna JakubowskaPaul A JamesUffe Birk JensenEsther M JohnMichael E JonesRudolf KaaksPooja Middha KapoorBeth Y KarlanRenske KeemanElza KhusnutdinovaJohanna I KiiskiYon-Dschun KoVeli-Matti KosmaPeter KraftAllison W KurianYael LaitmanDiether LambrechtsLoic Le MarchandJenny LesterFabienne LesueurTricia LindstromAdria Lopez-FernándezJennifer T LoudCraig LuccariniArto MannermaaSiranoush ManoukianSara MargolinJohn W M MartensNoura MebiroukAlfons MeindlAustin MillerJonathan BeesleyMarco MontagnaKatherine L NathansonSusan L NeuhausenHeli NevanlinnaFinn C NielsenKatie M O'BrienOlufunmilayo I OlopadeJanet E OlsonHåkan OlssonAna OsorioLaura OttiniTjoung-Won Park-SimonMichael T ParsonsInge Sokilde PedersenBeth N PeshkinPaolo PeterlongoJulian PetoPaul David Peter PharoahKelly-Anne PhillipsEric C PolleyBruce PoppeNadege PresneauMiquel Angel PujanaKevin PuniePaolo RadiceJohanna RantalaMuhammad U RashidGadi RennertHedy S RennertMark E RobsonAtocha RomeroMaria RossingEmmanouil SaloustrosDale R SandlerRegina SantellaMaren T ScheunerMarjanka K SchmidtGunnar SchmidtChristopher G ScottPriyanka SharmaPenny SoucyMelissa C SoutheyJohn J SpinelliZoe SteinsnyderJennifer StoneDominique Stoppa-LyonnetAnthony SwerdlowRulla M TamimiWilliam J TapperJack A TaylorMary Beth TerryAlex TeuléDarcy L ThullMarc TischkowitzAmanda Ewart TolandDiana TorresAlison H TrainerThérèse TruongNadine TungCeline M VachonAna VegaJoseph VijaiQin WangBarbara WappenschmidtClarice R WeinbergJeffrey N WeitzelCamilla WendtAlicja WolkSiddhartha YadavXiaohong R YangDrakoulis YannoukakosWei ZhengArgyrios ZiogasKristin K ZornSue-Kyung ParkMads ThomassenKenneth OffitRita K SchmutzlerFergus J CouchJacques SimardGeorgia Chenevix-TrenchDouglas F EastonNadine AndrieuAntonis C AntoniouPublished in: Nature communications (2021)
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.