Figlioli, GisellaBogliolo, MassimoCatucci, IreneCaleca, LauraLasheras, Sandra VizPujol, RoserKiiski, Johanna IMuranen, Taru ABarnes, Daniel RDennis, JoeMichailidou, KyriakiBolla, Manjeet KLeslie, GoskaAalfs, Cora MAdank, Muriel AAdlard, JulianAgata, SimonaCadoo, KarenAgnarsson, Bjarni AAhearn, ThomasAittomäki, KristiinaAmbrosone, Christine BAndrews, LesleyAnton-Culver, HodaAntonenkova, Natalia NArndt, VolkerArnold, NorbertAronson, Kristan JArun, Banu KAsseryanis, EllaAuber, BerndAuvinen, PäiviAzzollini, JacopoBalmaña, JudithBarkardottir, Rosa BBarrowdale, DanielBarwell, JulianBeane Freeman, Laura EBeauparlant, Charles JolyBeckmann, Matthias WBehrens, SabineBenitez, JavierBerger, RaananBermisheva, MarinaBlanco, Amie MBlomqvist, CarlBogdanova, Natalia VBojesen, AndersBojesen, Stig EBonanni, BernardoBorg, AkeBrady, Angela FBrauch, HiltrudBrenner, HermannBrüning, ThomasBurwinkel, BarbaraBuys, Saundra SCaldés, TrinidadCaliebe, AlmuthCaligo, Maria ACampa, DanieleCampbell, Ian GCanzian, FedericoCastelao, Jose EChang-Claude, JennyChanock, Stephen JClaes, Kathleen B MClarke, Christine LCollavoli, AnitaConner, Thomas ACox, David GCybulski, CezaryCzene, KamilaDaly, Mary Bde la Hoya, MiguelDevilee, PeterDiez, OrlandDing, Yuan ChunDite, Gillian SDitsch, NinaDomchek, Susan MDorfling, Cecilia MDos-Santos-Silva, IsabelDurda, KatarzynaDwek, MiriamEccles, Diana MEkici, Arif BEliassen, A HeatherEllberg, CarolinaEriksson, MikaelEvans, D GarethFasching, Peter AFigueroa, JonineFlyger, HenrikFoulkes, William DFriebel, Tara MFriedman, EitanGabrielson, MarikeGaddam, PragnaGago-Dominguez, ManuelaGao, ChiGapstur, Susan MGarber, JudyGarcía-Closas, MontserratGarcía-Sáenz, José AGaudet, Mia MGayther, Simon AGiles, Graham GGlendon, GordGodwin, Andrew KGoldberg, Mark SGoldgar, David EGuénel, PascalGutierrez-Barrera, Angelica MHaeberle, LotharHaiman, Christopher AHåkansson, NiclasHall, PerHamann, UteHarrington, Patricia AHein, AlexanderHeyworth, JaneHillemanns, PeterHollestelle, AntoinetteHopper, John LHosgood, H DeanHowell, AnthonyHu, ChunlingHulick, Peter JHunter, David JImyanitov, Evgeny NIsaacs, ClaudineJakimovska, MilenaJakubowska, AnnaJames, PaulJanavicius, RamunasJanni, WolfgangJohn, Esther MJones, Michael EJung, AudreyKaaks, RudolfKarlan, Beth YKhusnutdinova, ElzaKitahara, Cari MKonstantopoulou, IreneKoutros, StellaKraft, PeterLambrechts, DietherLazaro, ConxiLe Marchand, LoicLester, JennyLesueur, FabienneLilyquist, JennaLoud, Jennifer TLu, Karen HLuben, Robert NLubinski, JanMannermaa, ArtoManoochehri, MehdiManoukian, SiranoushMargolin, SaraMartens, John W MMaurer, TabeaMavroudis, DimitriosMebirouk, NouraMeindl, AlfonsMenon, UshaMiller, AustinMontagna, MarcoNathanson, Katherine LNeuhausen, Susan LNewman, William GNguyen-Dumont, TuNielsen, Finn CiliusNielsen, SarahNikitina-Zake, LieneOffit, KennethOlah, EdithOlopade, Olufunmilayo IOlshan, Andrew FOlson, Janet EOlsson, HåkanOsorio, AnaOttini, LauraPeissel, BernardPeixoto, AnaPeto, JulianPlaseska-Karanfilska, DijanaPocza, TimeaPresneau, NadegePujana, Miquel AngelPunie, KevinRack, BrigitteRantala, JohannaRashid, Muhammad URau-Murthy, RohiniRennert, GadLejbkowicz, FlavioRhenius, ValerieRomero, AtochaRookus, Matti ARoss, Eric ARossing, MariaRudaitis, ViliusRuebner, MatthiasSaloustros, EmmanouilSanden, KristinSantamariña, MartaScheuner, Maren TSchmutzler, Rita KSchneider, MichaelScott, ChristopherSenter, LeighaShah, MitulSharma, PriyankaShu, Xiao-OuSimard, JacquesSinger, Christian FSohn, ChristofSoucy, PennySouthey, Melissa CSpinelli, John JSteele, LindaStoppa-Lyonnet, DominiqueTapper, William JTeixeira, Manuel RTerry, Mary BethThomassen, MadsThompson, JenniferThull, Darcy LTischkowitz, MarcTollenaar, Rob A E MTorres, DianaTroester, Melissa ATruong, ThérèseTung, NadineUntch, MichaelVachon, Celine Mvan Rensburg, Elizabeth Jvan Veen, Elke MVega, AnaViel, AlessandraWappenschmidt, BarbaraWeitzel, Jeffrey NWendt, CamillaWieme, GreetWolk, AlicjaYang, Xiaohong RZheng, WeiZiogas, ArgyriosZorn, Kristin KDunning, Alison MLush, MichaelWang, QinMcGuffog, LesleyParsons, Michael TPharoah, Paul D PFostira, FlorentiaToland, Amanda EAndrulis, Irene LRamus, Susan JSwerdlow, Anthony JGreene, Mark HChung, Wendy KMilne, Roger LChenevix-Trench, GeorgiaDörk, ThiloSchmidt, Marjanka KEaston, Douglas FRadice, PaoloHahnen, EricAntoniou, Antonis CCouch, Fergus JNevanlinna, HeliSurrallés, JordiPeterlongo, Paolo2020-03-302020-03-302019-11-01NPJ Breast Cancer. 2019;5:38.2374-4677http://hdl.handle.net/20.500.12105/9372Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/Cancer geneticsAtribución-NoComercial-CompartirIgual 4.0 Internacional31700994513810.1038/s41523-019-0127-5NPJ breast canceropen access