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Repisalud author Figlioli, Gisella author Bogliolo, Massimo author Catucci, Irene author Caleca, Laura author Lasheras, Sandra Viz author Pujol, Roser author Kiiski, Johanna I author Muranen, Taru A author Barnes, Daniel R author Dennis, Joe author Michailidou, Kyriaki author Bolla, Manjeet K author Leslie, Goska author Aalfs, Cora M author Adank, Muriel A author Adlard, Julian author Agata, Simona author Cadoo, Karen author Agnarsson, Bjarni A author Ahearn, Thomas author Aittomäki, Kristiina author Ambrosone, Christine B author Andrews, Lesley author Anton-Culver, Hoda author Antonenkova, Natalia N author Arndt, Volker author Arnold, Norbert author Aronson, Kristan J author Arun, Banu K author Asseryanis, Ella author Auber, Bernd author Auvinen, Päivi author Azzollini, Jacopo author Balmaña, Judith author Barkardottir, Rosa B author Barrowdale, Daniel author Barwell, Julian author Beane Freeman, Laura E author Beauparlant, Charles Joly author Beckmann, Matthias W author Behrens, Sabine author Benitez, Javier author Berger, Raanan author Bermisheva, Marina author Blanco, Amie M author Blomqvist, Carl author Bogdanova, Natalia V author Bojesen, Anders author Bojesen, Stig E author Bonanni, Bernardo author Borg, Ake author Brady, Angela F author Brauch, Hiltrud author Brenner, Hermann author Brüning, Thomas author Burwinkel, Barbara author Buys, Saundra S author Caldés, Trinidad author Caliebe, Almuth author Caligo, Maria A author Campa, Daniele author Campbell, Ian G author Canzian, Federico author Castelao, Jose E author Chang-Claude, Jenny author Chanock, Stephen J author Claes, Kathleen B M author Clarke, Christine L author Collavoli, Anita author Conner, Thomas A author Cox, David G author Cybulski, Cezary author Czene, Kamila author Daly, Mary B author de la Hoya, Miguel author Devilee, Peter author Diez, Orland author Ding, Yuan Chun author Dite, Gillian S author Ditsch, Nina author Domchek, Susan M author Dorfling, Cecilia M author Dos-Santos-Silva, Isabel author Durda, Katarzyna author Dwek, Miriam author Eccles, Diana M author Ekici, Arif B author Eliassen, A Heather author Ellberg, Carolina author Eriksson, Mikael author Evans, D Gareth author Fasching, Peter A author Figueroa, Jonine author Flyger, Henrik author Foulkes, William D author Friebel, Tara M author Friedman, Eitan author Gabrielson, Marike author Gaddam, Pragna author Gago-Dominguez, Manuela author Gao, Chi author Gapstur, Susan M author Garber, Judy author García-Closas, Montserrat author García-Sáenz, José A author Gaudet, Mia M author Gayther, Simon A author Giles, Graham G author Glendon, Gord author Godwin, Andrew K author Goldberg, Mark S author Goldgar, David E author Guénel, Pascal author Gutierrez-Barrera, Angelica M author Haeberle, Lothar author Haiman, Christopher A author Håkansson, Niclas author Hall, Per author Hamann, Ute author Harrington, Patricia A author Hein, Alexander author Heyworth, Jane author Hillemanns, Peter author Hollestelle, Antoinette author Hopper, John L author Hosgood, H Dean author Howell, Anthony author Hu, Chunling author Hulick, Peter J author Hunter, David J author Imyanitov, Evgeny N author Isaacs, Claudine author Jakimovska, Milena author Jakubowska, Anna author James, Paul author Janavicius, Ramunas author Janni, Wolfgang author John, Esther M author Jones, Michael E author Jung, Audrey author Kaaks, Rudolf author Karlan, Beth Y author Khusnutdinova, Elza author Kitahara, Cari M author Konstantopoulou, Irene author Koutros, Stella author Kraft, Peter author Lambrechts, Diether author Lazaro, Conxi author Le Marchand, Loic author Lester, Jenny author Lesueur, Fabienne author Lilyquist, Jenna author Loud, Jennifer T author Lu, Karen H author Luben, Robert N author Lubinski, Jan author Mannermaa, Arto author Manoochehri, Mehdi author Manoukian, Siranoush author Margolin, Sara author Martens, John W M author Maurer, Tabea author Mavroudis, Dimitrios author Mebirouk, Noura author Meindl, Alfons author Menon, Usha author Miller, Austin author Montagna, Marco author Nathanson, Katherine L author Neuhausen, Susan L author Newman, William G author Nguyen-Dumont, Tu author Nielsen, Finn Cilius author Nielsen, Sarah author Nikitina-Zake, Liene author Offit, Kenneth author Olah, Edith author Olopade, Olufunmilayo I author Olshan, Andrew F author Olson, Janet E author Olsson, Håkan author Osorio, Ana author Ottini, Laura author Peissel, Bernard author Peixoto, Ana author Peto, Julian author Plaseska-Karanfilska, Dijana author Pocza, Timea author Presneau, Nadege author Pujana, Miquel Angel author Punie, Kevin author Rack, Brigitte author Rantala, Johanna author Rashid, Muhammad U author Rau-Murthy, Rohini author Rennert, Gad author Lejbkowicz, Flavio author Rhenius, Valerie author Romero, Atocha author Rookus, Matti A author Ross, Eric A author Rossing, Maria author Rudaitis, Vilius author Ruebner, Matthias author Saloustros, Emmanouil author Sanden, Kristin author Santamariña, Marta author Scheuner, Maren T author Schmutzler, Rita K author Schneider, Michael author Scott, Christopher author Senter, Leigha author Shah, Mitul author Sharma, Priyanka author Shu, Xiao-Ou author Simard, Jacques author Singer, Christian F author Sohn, Christof author Soucy, Penny author Southey, Melissa C author Spinelli, John J author Steele, Linda author Stoppa-Lyonnet, Dominique author Tapper, William J author Teixeira, Manuel R author Terry, Mary Beth author Thomassen, Mads author Thompson, Jennifer author Thull, Darcy L author Tischkowitz, Marc author Tollenaar, Rob A E M author Torres, Diana author Troester, Melissa A author Truong, Thérèse author Tung, Nadine author Untch, Michael author Vachon, Celine M author van Rensburg, Elizabeth J author van Veen, Elke M author Vega, Ana author Viel, Alessandra author Wappenschmidt, Barbara author Weitzel, Jeffrey N author Wendt, Camilla author Wieme, Greet author Wolk, Alicja author Yang, Xiaohong R author Zheng, Wei author Ziogas, Argyrios author Zorn, Kristin K author Dunning, Alison M author Lush, Michael author Wang, Qin author McGuffog, Lesley author Parsons, Michael T author Pharoah, Paul D P author Fostira, Florentia author Toland, Amanda E author Andrulis, Irene L author Ramus, Susan J author Swerdlow, Anthony J author Greene, Mark H author Chung, Wendy K author Milne, Roger L author Chenevix-Trench, Georgia author Dörk, Thilo author Schmidt, Marjanka K author Easton, Douglas F author Radice, Paolo author Hahnen, Eric author Antoniou, Antonis C author Couch, Fergus J author Nevanlinna, Heli author Surrallés, Jordi author Peterlongo, Paolo funder Ministerio de Economía y Competitividad (España) funder Unión Europea. Comisión Europea funder Against Breast Cancer funder Cancer Research UK (Reino Unido) funder Unión Europea. Comisión Europea. H2020 funder Cancer UK Grant funder Canadian Institutes of Health Research funder Ministère de Économie, de la science et de innovation (Canadá) funder NIH - National Cancer Institute (NCI) (Estados Unidos) funder Dutch Cancer Society (Holanda) funder Instituto de Salud Carlos III funder Xunta de Galicia (España) funder Canadian Cancer Society funder California Breast Cancer Research Program funder California Department of Public Health funder Medical Research Council (Reino Unido) funder Free State of Saxony, Germany (LIFE -Leipzig Research Centre for Civilization Diseases) funder German Cancer Aid funder Helsinki University Hospital funder Finlands Akademi (Finlandia) funder Deutsche Forschungsgemeinschaft (Alemania) funder Federal Ministry of Education & Research (Alemania) funder Russian Foundation for Basic Research funder Ministry of Science and Higher Education (Rusia) funder National Health and Medical Research Council (Australia) funder Biobanking and BioMolecular resources Research Infrastructure (Países Bajos) funder Estée Lauder Companies’ Breast Cancer Campaign funder Swedish Research Council funder NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos) funder Lon V. Smith Foundation funder Lietuvos Mokslo Taryba (Lituania) funder Italian Association for Cancer Research funder University of Kansas. Cancer Center (Estados Unidos) funder Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) funder French National Cancer Institute funder Netherlands Organisation for Health Research and Development funder Pink Ribbons Project funder United States Department of Health and Human Services 2020-03-30T15:03:49Z 2020-03-30T15:03:49Z 2019-11-01 NPJ Breast Cancer. 2019;5:38. 10.1038/s41523-019-0127-5 2374-4677 NPJ breast cancer 31700994 http://hdl.handle.net/20.500.12105/9372 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. eng Cancer genetics The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer journal article 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 URL https://repisalud.isciii.es/bitstreams/d2d70163-7b76-42ec-9d4a-1778898bdc0c/download File MD5 a1ff4a4aece0841183e1553e2aa9545f 1914642 application/pdf TheFANCMp.Arg658 truncatin_2019.pdf URL https://repisalud.isciii.es/bitstreams/0e6cc1cd-ccd1-41c0-8c5c-4e55a2685006/download File MD5 5fe391d4096442819c0d7c41a61e11cc 127751 text/plain TheFANCMp.Arg658 truncatin_2019.pdf.txt