The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Gisella FiglioliMassimo BoglioloIrene CatucciLaura CalecaSandra Viz LasherasRoser PujolJohanna I KiiskiTaru A MuranenDaniel R BarnesJoe G DennisKyriaki MichailidouManjeet K BollaGoska LeslieCora M Aalfsnull nullMuriel A AdankJulian AdlardSimona AgataKaren CadooBjarni A AgnarssonThomas AhearnKristiina AittomäkiChristine B AmbrosoneLesley AndrewsHoda Anton-CulverNatalia N AntonenkovaVolker ArndtNorbert ArnoldKristan J AronsonBanu K ArunElla AsseryanisBernd AuberPäivi AuvinenJacopo AzzolliniJudith BalmañaRosa B BarkardottirDaniel BarrowdaleJulian BarwellLaura E Beane FreemanCharles Joly BeauparlantMatthias W BeckmannSabine BehrensJavier BenitezRaanan BergerMarina BermishevaAmie M BlancoCarl BlomqvistNatalia V BogdanovaAnders BojesenStig E BojesenBernardo BonanniAke BorgAngela F BradyHiltrud B BrauchHermann BrennerThomas BrüningBarbara BurwinkelSaundra S BuysTrinidad CaldésAlmuth CaliebeMaria A CaligoDaniele CampaIan G CampbellFederico CanzianJose E CastelaoJenny Chang-ClaudeStephen J ChanockKathleen B M ClaesChristine L ClarkeAnita CollavoliThomas A ConnerDavid G CoxCezary CybulskiKamila CzeneMary B DalyMiguel de la HoyaPeter DevileeOrland DiezYuan Chun DingGillian S DiteNina DitschSusan M DomchekCecilia M DorflingIsabel Dos-Santos-SilvaKatarzyna DurdaMiriam DwekDiana M EcclesArif B EkiciA Heather EliassenCarolina EllbergMikael ErikssonD Gareth EvansPeter A FaschingJonine FigueroaHenrik FlygerWilliam D FoulkesTara M FriebelEitan FriedmanMarike GabrielsonPragna GaddamManuela Gago-DominguezChi GaoSusan M GapsturJudy GarberMontserrat García-ClosasJosé A García-SáenzMia M GaudetSimon A Gaythernull nullGraham G GilesGord GlendonAndrew K GodwinMark S GoldbergDavid E GoldgarPascal GuénelAngelica M Gutierrez-BarreraLothar HaeberleChristopher A HaimanNiclas HåkanssonPer HallUte HamannPatricia A HarringtonAlexander HeinJane HeyworthPeter HillemannsAntoinette HollestelleJohn L HopperH Dean HosgoodAnthony HowellChunling HuPeter J HulickDavid J HunterEvgeny N Imyanitovnull nullClaudine Isaacs Milena Jakimovska ÖzdemirAnna JakubowskaPaul JamesRamunas JanaviciusWolfgang JanniEsther M JohnMichael E JonesAudrey JungRudolf KaaksBeth Y KarlanElza KhusnutdinovaCari M KitaharaIrene KonstantopoulouStella KoutrosPeter KraftDiether LambrechtsConxi LazaroLoic Le MarchandJenny LesterFabienne LesueurJenna LilyquistJennifer T LoudKaren H LuRobert N LubenJan LubinskiArto MannermaaMehdi ManoochehriSiranoush ManoukianSara MargolinJohn W M MartensTabea MaurerDimitrios MavroudisNoura MebiroukAlfons MeindlUsha Menon Austin MillerMarco MontagnaKatherine L NathansonSusan L NeuhausenWilliam G NewmanTu Nguyen-DumontFinn Cilius NielsenSarah NielsenLiene Nikitina-ZakeKenneth OffitEdith OlahOlufunmilayo I OlopadeAndrew F OlshanJanet E OlsonHåkan OlssonAna OsorioLaura OttiniBernard PeisselAna PeixotoJulian PetoDijana Plaseska-KaranfilskaTimea PoczaNadege PresneauMiquel Angel PujanaKevin PunieBrigitte RackJohanna RantalaMuhammad U RashidRohini Rau-MurthyGad RennertFlavio LejbkowiczValerie RheniusAtocha RomeroMatti A RookusEric A RossMaria RossingVilius RudaitisMatthias RuebnerEmmanouil SaloustrosKristin SandenMarta SantamariñaMaren T ScheunerRita K SchmutzlerMichael SchneiderChristopher G ScottLeigha SenterMitul ShahPriyanka SharmaXiao-Ou ShuJacques SimardChristian F SingerChristof SohnPenny SoucyMelissa C SoutheyJohn J SpinelliLinda SteeleDominique Stoppa-LyonnetWilliam J TapperManuel R TeixeiraMary Beth TerryMads ThomassenJennifer ThompsonDarcy L ThullMarc TischkowitzRob A E M TollenaarDiana TorresMelissa A TroesterThérèse TruongNadine TungMichael UntchCeline M VachonElizabeth J van RensburgElke M van VeenAna VegaAlessandra VielBarbara WappenschmidtJeffrey N WeitzelCamilla WendtGreet WiemeAlicja WolkXiaohong R YangQuan Long Argyrios ZiogasKristin K ZornAlison M DunningMichael LushQin WangLesley McGuffogMichael T ParsonsPaul D P PharoahFlorentia FostiraAmanda E TolandIrene L AndrulisSusan J RamusAnthony J SwerdlowMark H GreeneWendy K ChungRoger L MilneGeorgia Chenevix-TrenchThilo DörkMarjanka K SchmidtDouglas F EastonPaolo RadiceEric HahnenAntonis C AntoniouFergus J CouchHeli NevanlinnaJordi SurrallésPaolo Peterlongo

Published in: NPJ breast cancer (2019)

Breast 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.