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The FANCM:p.Arg658* Truncating Variant is Associated with Risk of Triple-Negative Breast Cancer

Citation

Figlioli, Gisella; Bogliolo, Massimo; Catucci, Irene; Caleca, Laura; Lasheras, Sandra Viz; Pujol, Roser; Kiiski, Johanna I.; Muranen, Taru A.; Barnes, Daniel R.; & Dennis, Joe, et al. (2019). The FANCM:p.Arg658* Truncating Variant is Associated with Risk of Triple-Negative Breast Cancer. NPJ Breast Cancer, 5, 38. PMCID: PMC6825205

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.

URL

http://dx.doi.org/10.1038/s41523-019-0127-5

Reference Type

Journal Article

Journal Title

NPJ Breast Cancer

Author(s)

Figlioli, Gisella
Bogliolo, Massimo
Catucci, Irene
Caleca, Laura
Lasheras, Sandra Viz
Pujol, Roser
Kiiski, Johanna I.
Muranen, Taru A.
Barnes, Daniel R.
Dennis, Joe
Michailidou, Kyriaki
Bolla, Manjeet K.
Leslie, Goska
Aalfs, Cora M.
ABCTB Investigators
Adank, Muriel A.
Adlard, Julian
Agata, Simona
Cadoo, Karen
Agnarsson, Bjarni A.
Ahearn, Thomas
Aittomäki, 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, Päivi
Azzollini, Jacopo
Balmaña, Judith
Barkardottir, Rosa B.
Barrowdale, Daniel
Barwell, Julian
Beane Freeman, Laura E.
Beauparlant, Charles Joly
Beckmann, Matthias W.
Behrens, Sabine
Benitez, Javier
Berger, Raanan
Bermisheva, Marina
Blanco, Amie M.
Blomqvist, Carl
Bogdanova, Natalia V.
Bojesen, Anders
Bojesen, Stig Egil
Bonanni, Bernardo
Borg, Ake
Brady, Angela F.
Brauch, Hiltrud
Brenner, Hermann
Brüning, Thomas
Burwinkel, Barbara
Buys, Saundra S.
Caldés, Trinidad
Caliebe, Almuth
Caligo, Maria A.
Campa, Daniele
Campbell, Ian G.
Canzian, Federico
Castelao, Jose E.
Chang-Claude, Jenny
Chanock, Stephen J.
Claes, Kathleen B. M.
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
García-Closas, Montserrat
García-Sáenz, José A.
Gaudet, Mia M.
Gayther, Simon A.
GEMO Study Collaborators
Giles, Graham G.
Glendon, Gord
Godwin, Andrew K.
Goldberg, Mark S.
Goldgar, David E.
Guénel, Pascal
Gutierrez-Barrera, Angelica M.
Haeberle, Lothar
Haiman, Christopher A.
Håkansson, 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.
KConFab
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 W. M.
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 I.
Olshan, Andrew F.
Olson, Janet E.
Olsson, Håkan
Osorio, Ana
Ottini, Laura
Peissel, Bernard
Peixoto, Ana
Peto, Julian
Plaseska-Karanfilska, Dijana
Pocza, Timea
Presneau, Nadege
Pujana, Miquel Angel
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
Santamariña, 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 A. E. M.
Torres, Diana
Troester, Melissa A.
Truong, Thérèse
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 D. P.
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
Dörk, Thilo
Schmidt, Marjanka K.
Easton, Douglas F.
Radice, Paolo
Hahnen, Eric
Antoniou, Antonis C.
Couch, Fergus J.
Nevanlinna, Heli
Surrallés, Jordi
Peterlongo, Paolo

Year Published

2019

Volume Number

5

Pages

38

PMCID

PMC6825205

Reference ID

13068