npj Breast Cancer
Publication date:
2019-11-01
Publisher:
Nature Portfolio
Author:
Figlioli, Gisella
Bogliolo, Massimo ; Catucci, Irene ; Caleca, Laura ; Viz Lasheras, Sandra ; Pujol, Roser ; Kiiski, Johanna ; Muranen, Taru A ; Barnes, Daniel R ; Dennis, Joe ; Michailidou, Kyriaki ; Bolla, Manjeet K ; Leslie, Goska ; Aalfs, Cora M ; Adank, Muriel A ; Adlard, Julian ; Agata, Simona ; Cadoo, Karen ; Agnarsson, Bjarni A ; Ahearn, Thomas ; Aittomaki, Kristiina ; Ambrosone, Christine B ; Andrews, Lesley ; Anton-Culver, Hoda ; Antonenkova, Natalia N ; Arndt, Volker ; Arnold, Norbert ; Aronson, Kristan J ; Arun, Banu K ; Asseryanis, Ella ; Auber, Bernd ; Auvinen, Paivi ; Azzollini, Jacopo ; Balmana, Judith ; Barkardottir, Rosa B ; Barrowdale, Daniel ; Barwell, Julian ; Freeman, Laura E Beane ; Beauparlant, Charles Joly ; Beckmann, Matthias W ; Behrens, Sabine ; Benitez, Javier ; Berger, Raanan ; Bermisheva, Marina ; Blanco, Amie M ; Blomqvist, Carl ; Bogdanova, Natalia ; Bojesen, Anders ; Bojesen, Stig E ; Bonanni, Bernardo ; Borg, Ake ; Brady, Angela F ; Brauch, Hiltrud ; Brenner, Hermann ; Bruening, Thomas ; Burwinkel, Barbara ; Buys, Saundra S ; Caldes, Trinidad ; Caliebe, Almuth ; Caligo, Maria A ; Campa, Daniele ; Campbell, Ian G ; Canzian, Federico ; Castelao, Jose E ; Chang-Claude, Jenny ; Chanock, Stephen J ; Claes, Kathleen BM ; Clarke, Christine L ; Collavoli, Anita ; Conner, Thomas A ; Cox, David G ; Cybulski, Cezary ; Czene, Kamila ; Daly, Mary B ; de la Hoya, Miguel ; Devilee, Peter ; Diez, Orland ; Ding, Yuan Chun ; Dite, Gillian S ; Ditsch, Nina ; Domchek, Susan M ; Dorfling, Cecilia M ; dos-Santos-Silva, Isabel ; Durda, Katarzyna ; Dwek, Miriam ; Eccles, Diana M ; Ekici, Arif B ; Eliassen, A Heather ; Ellberg, Carolina ; Eriksson, Mikael ; Evans, D Gareth ; Fasching, Peter A ; Figueroa, Jonine ; Flyger, Henrik ; Foulkes, William D ; Friebel, Tara M ; Friedman, Eitan ; Gabrielson, Marike ; Gaddam, Pragna ; Gago-Dominguez, Manuela ; Gao, Chi ; Gapstur, Susan M ; Garber, Judy ; Garcia-Closas, Montserrat ; Garcia-Saenz, Jose A ; Gaudet, Mia M ; Gayther, Simon A ; Giles, Graham G ; Glendon, Gord ; Godwin, Andrew K ; Goldberg, Mark S ; Goldgar, David E ; Guenel, Pascal ; Gutierrez-Barrera, Angelica M ; Haeberle, Lothar ; Haiman, Christopher A ; Hakansson, Niclas ; Hall, Per ; Hamann, Ute ; Harrington, Patricia A ; Hein, Alexander ; Heyworth, Jane ; Hillemanns, Peter ; Hollestelle, Antoinette ; Hopper, John L ; Hosgood, H Dean ; Howell, Anthony ; Hu, Chunling ; Hulick, Peter J ; Hunter, David J ; Imyanitov, Evgeny N ; Isaacs, Claudine ; Jakimovska, Milena ; Jakubowska, Anna ; James, Paul ; Janavicius, Ramunas ; Janni, Wolfgang ; John, Esther M ; Jones, Michael E ; Jung, Audrey ; Kaaks, Rudolf ; Karlan, Beth Y ; Khusnutdinova, Elza ; Kitahara, Cari M ; Konstantopoulou, Irene ; Koutros, Stella ; Kraft, Peter ; Lambrechts, Diether ; Lazaro, Conxi ; Le Marchand, Loic ; Lester, Jenny ; Lesueur, Fabienne ; Lilyquist, Jenna ; Loud, Jennifer T ; Lu, Karen H ; Luben, Robert N ; Lubinski, Jan ; Mannermaa, Arto ; Manoochehri, Mehdi ; Manoukian, Siranoush ; Margolin, Sara ; Martens, John WM ; Maurer, Tabea ; Mavroudis, Dimitrios ; Mebirouk, Noura ; Meindl, Alfons ; Menon, Usha ; Miller, Austin ; Montagna, Marco ; Nathanson, Katherine L ; Neuhausen, Susan L ; Newman, William G ; Nguyen-Dumont, Tu ; Nielsen, Finn Cilius ; Nielsen, Sarah ; Nikitina-Zake, Liene ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo ; Olshan, Andrew F ; Olson, Janet E ; Olsson, Hakan ; Osorio, Ana ; Ottini, Laura ; Peissel, Bernard ; Peixoto, Ana ; Peto, Julian ; Plaseska-Karanfilska, Dijana ; Pocza, Timea ; Presneau, Nadege ; Angel Pujana, Miquel ; Punie, Kevin ; Rack, Brigitte ; Rantala, Johanna ; Rashid, Muhammad U ; Rau-Murthy, Rohini ; Rennert, Gad ; Lejbkowicz, Flavio ; Rhenius, Valerie ; Romero, Atocha ; Rookus, Matti A ; Ross, Eric A ; Rossing, Maria ; Rudaitis, Vilius ; Ruebner, Matthias ; Saloustros, Emmanouil ; Sanden, Kristin ; Santamarina, Marta ; Scheuner, Maren T ; Schmutzler, Rita K ; Schneider, Michael ; Scott, Christopher ; Senter, Leigha ; Shah, Mitul ; Sharma, Priyanka ; Shu, Xiao-Ou ; Simard, Jacques ; Singer, Christian F ; Sohn, Christof ; Soucy, Penny ; Southey, Melissa C ; Spinelli, John J ; Steele, Linda ; Stoppa-Lyonnet, Dominique ; Tapper, William J ; Teixeira, Manuel R ; Terry, Mary Beth ; Thomassen, Mads ; Thompson, Jennifer ; Thull, Darcy L ; Tischkowitz, Marc ; Tollenaar, Rob AEM ; Torres, Diana ; Troester, Melissa A ; Truong, Therese ; Tung, Nadine ; Untch, Michael ; Vachon, Celine M ; van Rensburg, Elizabeth J ; van Veen, Elke M ; Vega, Ana ; Viel, Alessandra ; Wappenschmidt, Barbara ; Weitzel, Jeffrey N ; Wendt, Camilla ; Wieme, Greet ; Wolk, Alicja ; Yang, Xiaohong R ; Zheng, Wei ; Ziogas, Argyrios ; Zorn, Kristin K ; Dunning, Alison M ; Lush, Michael ; Wang, Qin ; McGuffog, Lesley ; Parsons, Michael T ; Pharoah, Paul DP ; Fostira, Florentia ; Toland, Amanda E ; Andrulis, Irene L ; Ramus, Susan J ; Swerdlow, Anthony J ; Greene, Mark H ; Chung, Wendy K ; Milne, Roger L ; Chenevix-Trench, Georgia ; Doerk, Thilo ; Schmidt, Marjanka K ; Easton, Douglas F ; Radice, Paolo ; Hahnen, Eric ; Antoniou, Antonis C ; Couch, Fergus J ; Nevanlinna, Heli ; Surralles, Jordi ; Peterlongo, Paolo ; Balleine, Rosemary ; Baxter, Robert ; Braye, Stephen ; Carpenter, Jane ; Dahlstrom, Jane ; Forbes, John ; Lee, C Soon ; Marsh, Deborah ; Morey, Adrienne ; Pathmanathan, Nirmala ; Scott, Rodney ; Simpson, Peter ; Spigelman, Allan ; Wilcken, Nicholas ; Yip, Desmond ; Zeps, Nikolajs ; Belotti, Muriel ; Bertrand, Ophelie ; Birot, Anne-Marie ; Buecher, Bruno ; Caputo, Sandrine ; Dupre, Anais ; Fourme, Emmanuelle ; Gauthier-Villars, Marion ; Golmard, Lisa ; Le Mentec, Marine ; Moncoutier, Virginie ; de Pauw, Antoine ; Saule, Claire ; Boutry-Kryza, Nadia ; Calender, Alain ; Giraud, Sophie ; Leone, Mlanie ; Bressac-de-Paillerets, Brigitte ; Caron, Olivier ; Guillaud-Bataille, Marine ; Bignon, Yves-Jean ; Uhrhammer, Nancy ; Bonadona, Valerie ; Lasset, Christine ; Berthet, Pascaline ; Castera, Laurent ; Vaur, Dominique ; Bourdon, Violaine ; Nogues, Catherine ; Noguchi, Tetsuro ; Popovici, Cornel ; Remenieras, Audrey ; Sobol, Hagay ; Coupier, Isabelle ; Pujol, Pascal ; Adenis, Claude ; Dumont, Aurelie ; Revillion, Francoise ; Muller, Daniele ; Barouk-Simonet, Emmanuelle ; Bonnet, Francoise ; Bubien, Virginie ; Longy, Michel ; Sevenet, Nicolas ; Gladieff, Laurence ; Guimbaud, Rosine ; Feillel, Viviane ; Toulas, Christine ; Dreyfus, Helene ; Leroux, Christine Dominique ; Peysselon, Magalie ; Rebischung, Christine ; Legrand, Clementine ; Baurand, Amandine ; Bertolone, Geoffrey ; Coron, Fanny ; Faivre, Laurence ; Jacquot, Caroline ; Lizard, Sarab ; Kientz, Caroline ; Lebrun, Marine ; Prieur, Fabienne ; Fert-Ferrer, Sandra ; Mari, Vronique ; Venat-Bouvet, Laurence ; Bezieau, Stephane ; Delnatte, Capucine ; Mortemousque, Isabelle ; Colas, Chrystelle ; Coulet, Florence ; Soubrier, Florent ; Warcoin, Mathilde ; Bronner, Myriam ; Sokolowska, Johanna ; Collonge-Rame, Marie-Agnes ; Damette, Alexandre ; Gesta, Paul ; Lallaoui, Hakima ; Chiesa, Jean ; Molina-Gomes, Denise ; Ingster, Olivier ; Manouvrier-Hanu, Sylvie ; Lejeune, Sophie ; Aghmesheh, Morteza ; Greening, Sian ; Amor, David ; Gattas, Mike ; Botes, Leon ; Buckley, Michael ; Friedlander, Michael ; Koehler, Jessica ; Meiser, Bettina ; Saleh, Mona ; Salisbury, Elizabeth ; Trainer, Alison ; Tucker, Kathy ; Antill, Yoland ; Dobrovic, Alexander ; Fellows, Andrew ; Fox, Stephen ; Harris, Marion ; Nightingale, Sophie ; Phillips, Kelly ; Sambrook, Joe ; Thorne, Heather ; Armitage, Shane ; Arnold, Leanne ; Kefford, Rick ; Kirk, Judy ; Rickard, Edwina ; Bastick, Patti ; Beesley, Jonathan ; Hayward, Nick ; Spurdle, Amanda ; Walker, Logan ; Beilby, John ; Saunders, Christobel ; Bennett, Ian ; Blackburn, Anneke ; Bogwitz, Michael ; Gaff, Clara ; Lindeman, Geoff ; Pachter, Nick ; Scott, Clare ; Sexton, Adrienne ; Visvader, Jane ; Taylor, Jessica ; Winship, Ingrid ; Brennan, Meagan ; Brown, Melissa ; French, Juliet ; Edwards, Stacey ; Burgess, Matthew ; Burke, Jo ; Patterson, Briony ; Butow, Phyllis ; Culling, Bronwyn ; Caldon, Liz ; Callen, David ; Chauhan, Deepa ; Eisenbruch, Maurice ; Heiniger, Louise ; Chauhan, Manisha ; Christian, Alice ; Dixon, Joanne ; Kidd, Alexa ; Cohen, Paul ; Colley, Alison ; Fenton, Georgina ; Crook, Ashley ; Dickson, Rebecca ; Field, Michael ; Cui, James ; Cummings, Margaret ; Dawson, Sarah-Jane ; DeFazio, Anna ; Delatycki, Martin ; Dudding, Tracy ; Edkins, Ted ; Farshid, Gelareh ; Flanagan, James ; Fong, Peter ; Forrest, Laura ; Gallego-Ortega, David ; George, Peter ; Gill, Grantley ; Kollias, James ; Haan, Eric ; Hart, Stewart ; Jenkins, Mark ; Hunt, Clare ; Lakhani, Sunil ; Lipton, Lara ; Lobb, Liz ; Mann, Graham ; McLachlan, Sue Anne ; O'Connell, Shona ; O'Sullivan, Sarah ; Pieper, Ellen ; Robinson, Bridget ; Saunus, Jodi ; Scott, Elizabeth ; Shelling, Andrew ; Williams, Rachael ; Young, Mary Ann
Keywords:
Science & Technology, Life Sciences & Biomedicine, Oncology, FANCONI-ANEMIA, GENE, C.5791C-GREATER-THAN-T, MUTATIONS, Cancer genetics, ABCTB Investigators, GEMO Study Collaborators, KConFab, 3202 Clinical sciences, 3211 Oncology and carcinogenesis, 4202 Epidemiology
Abstract:
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.