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

Gisella Figlioli, Massimo Bogliolo, Irene Catucci, Laura Caleca, Sandra Viz Lasheras, Roser Pujol, Johanna I. Kiiski, Taru A. Muranen, Daniel R. Barnes, Joe Dennis, Kyriaki Michailidou, Manjeet K. Bolla, Goska Leslie, Cora M. Aalfs, ABCTB Investigators, Muriel A. Adank, Julian Adlard, Simona Agata, Karen Cadoo, Bjarni A. AgnarssonThomas Ahearn, Kristiina Aittomäki, Christine B. Ambrosone, Lesley Andrews, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Bernd Auber, Päivi Auvinen, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Julian Barwell, Laura E. Beane Freeman, Charles Joly Beauparlant, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Raanan Berger, Marina Bermisheva, Amie M. Blanco, Carl Blomqvist, Natalia V. Bogdanova, Anders Bojesen, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Angela F. Brady, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Daniele Campa, Ian G. Campbell, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Kathleen B. M. Claes, Christine L. Clarke, Anita Collavoli, Thomas A. Conner, David G. Cox, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Nina Ditsch, Susan M. Domchek, Cecilia M. Dorfling, Isabel dos-Santos-Silva, Katarzyna Durda, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, William D. Foulkes, Tara M. Friebel, Eitan Friedman, Marike Gabrielson, Pragna Gaddam, Manuela Gago-Dominguez, Chi Gao, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, GEMO Study Collaborators, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Pascal Guénel, Angelica M. Gutierrez-Barrera, Lothar Haeberle, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, John L. Hopper, H. Dean Hosgood, Anthony Howell, Chunling Hu, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, kConFab, Louise Heiniger, Georgina Fenton, Claudine Issacs, Milena Jakimovska, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolph Kaaks, Beth Y. Karlan, Elza Khusnutdinova, Cari M. Kitahara, Irene Konstantopoulou, Stella Koutros, Peter Kraft, Diether Lambrects, Conxi Lazaro, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Jenna Lilyquist, Jennifer T. Loud, Karen H. Lu, Robert N. Luben, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Tabea Maurer, Dimitrios Mavroudis, Noura Mebirouk, Alfons Meindl, Usha Menon, Austin Miller, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, William G. Newman, Tu Nguyen-Dumont, Finn Cilius Nielsen, Sarah Nielsen, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Bernard Peissel, Ana Peixoto, Julian Peto, Dijana Plaseska-Karanfilska, Timea Pocza, Nadège Presneau, Miquel Angel Pujana, Kevin Punie, Brigitte Rack, Johanna Rantala, Muhammad U. Rashid, Rohini Rau-Murthy, Gad Rennert, Flavio Lejbkowicz, Valerie Rhenius, Atocha Romero, Matti A. Rookus, Eric A. Ross, Maria Rossing, Vilius Rudaitis, Mattias Ruebner, Emmanouil Saloustros, Kristin Sanden, Marta Santamarina, Maren T. Scheuner, Rita K. Schmutzler, Michael Schneider, Christopher Scott, Leigha Senter, Mitul Shah, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Linda Steele, Dominique Stoppa-Lyonnet, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Mads Thomassen, Jennifer Thompson, Darcy L. Thull, Marc Tischkowitz, Rob A. E. M. Tollenaar, Diana Torres, Melissa A. Troester, Therese Truong, Nadine Tung, Michael Untch, Celine M. Vachon, Elizabeth J. van Rensburg, Elke M. van Veen, Ana Vega, Alessandra Viel, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Greet Wieme, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Alison M. Dunning, Michael Lush, Qin Wang, Lesley McGuffog, Michael T. Parsons, Paul D. P. Pharoah, Florentia Fostira, Amanda E. Toland, Irene L. Andrulis, Susan J. Ramus, Anthony J. Swerdlow, Mark H. Greene, Wendy K. Chung, Roger L. Milne, Georgia Chenevix-Trench, Thilo Dörk, Marjanka K. Schmidt, Douglas F. Easton, Paolo Radice, Eric Hahnen, Antonis C. Antoniou, Fergus J. Couch, Heli Nevanlinna, Jordi Surralles, Paolo Peterlongo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Article number38
Pages (from-to)1-14
Number of pages14
Journalnpj Breast Cancer
Volume5
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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