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 language | English |
|---|---|
| Article number | 38 |
| Number of pages | 14 |
| Journal | npj Breast Cancer |
| Volume | 5 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2019 |
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In: npj Breast Cancer, Vol. 5, No. 1, 38, 01.12.2019.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
AU - Figlioli, Gisella
AU - Bogliolo, Massimo
AU - Catucci, Irene
AU - Caleca, Laura
AU - Lasheras, Sandra Viz
AU - Pujol, Roser
AU - Kiiski, Johanna I.
AU - Muranen, Taru A.
AU - Barnes, Daniel R.
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Leslie, Goska
AU - Aalfs, Cora M.
AU - Balleine, Rosemary
AU - Baxter, Robert
AU - Braye, Stephen
AU - Carpenter, Jane
AU - Dahlstrom, Jane
AU - Forbes, John
AU - Lee, C. Soon
AU - Marsh, Deborah
AU - Morey, Adrienne
AU - Pathmanathan, Nirmala
AU - Scott, Rodney
AU - Simpson, Peter
AU - Spigelman, Allan
AU - Wilcken, Nicholas
AU - Yip, Desmond
AU - Zeps, Nikolajs
AU - Adank, Muriel A.
AU - Adlard, Julian
AU - Agata, Simona
AU - Cadoo, Karen
AU - Agnarsson, Bjarni A.
AU - Ahearn, Thomas
AU - Aittomäki, Kristiina
AU - Ambrosone, Christine B.
AU - Andrews, Lesley
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia N.
AU - Arndt, Volker
AU - Arnold, Norbert
AU - Aronson, Kristan J.
AU - Arun, Banu K.
AU - Asseryanis, Ella
AU - Auber, Bernd
AU - Auvinen, Päivi
AU - Azzollini, Jacopo
AU - Balmaña, Judith
AU - Barkardottir, Rosa B.
AU - Barrowdale, Daniel
AU - Barwell, Julian
AU - Beane Freeman, Laura E.
AU - Beauparlant, Charles Joly
AU - Beckmann, Matthias W.
AU - Behrens, Sabine
AU - Benitez, Javier
AU - Berger, Raanan
AU - Bermisheva, Marina
AU - Blanco, Amie M.
AU - Blomqvist, Carl
AU - Bogdanova, Natalia V.
AU - Bojesen, Anders
AU - Bojesen, Stig E.
AU - Bonanni, Bernardo
AU - Borg, Ake
AU - Brady, Angela F.
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Buys, Saundra S.
AU - Caldés, Trinidad
AU - Caliebe, Almuth
AU - Caligo, Maria A.
AU - Campa, Daniele
AU - Campbell, Ian G.
AU - Canzian, Federico
AU - Castelao, Jose E.
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Claes, Kathleen B.M.
AU - Clarke, Christine L.
AU - Collavoli, Anita
AU - Conner, Thomas A.
AU - Cox, David G.
AU - Cybulski, Cezary
AU - Czene, Kamila
AU - Daly, Mary B.
AU - de la Hoya, Miguel
AU - Devilee, Peter
AU - Diez, Orland
AU - Ding, Yuan Chun
AU - Dite, Gillian S.
AU - Ditsch, Nina
AU - Domchek, Susan M.
AU - Dorfling, Cecilia M.
AU - dos-Santos-Silva, Isabel
AU - Durda, Katarzyna
AU - Dwek, Miriam
AU - Eccles, Diana M.
AU - Ekici, Arif B.
AU - Eliassen, A. Heather
AU - Ellberg, Carolina
AU - Eriksson, Mikael
AU - Evans, D. Gareth
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Flyger, Henrik
AU - Foulkes, William D.
AU - Friebel, Tara M.
AU - Friedman, Eitan
AU - Gabrielson, Marike
AU - Gaddam, Pragna
AU - Gago-Dominguez, Manuela
AU - Gao, Chi
AU - Gapstur, Susan M.
AU - Garber, Judy
AU - García-Closas, Montserrat
AU - García-Sáenz, José A.
AU - Gaudet, Mia M.
AU - Gayther, Simon A.
AU - Belotti, Muriel
AU - Bertrand, Ophélie
AU - Birot, Anne Marie
AU - Buecher, Bruno
AU - Caputo, Sandrine
AU - Dupré, Anaïs
AU - Fourme, Emmanuelle
AU - Gauthier-Villars, Marion
AU - Golmard, Lisa
AU - Le Mentec, Marine
AU - Moncoutier, Virginie
AU - de Pauw, Antoine
AU - Saule, Claire
AU - Boutry-Kryza, Nadia
AU - Calender, Alain
AU - Giraud, Sophie
AU - Léone, Mélanie
AU - Bressac-de-Paillerets, Brigitte
AU - Caron, Olivier
AU - Guillaud-Bataille, Marine
AU - Bignon, Yves Jean
AU - Uhrhammer, Nancy
AU - Bonadona, Valérie
AU - Lasset, Christine
AU - Berthet, Pascaline
AU - Castera, Laurent
AU - Vaur, Dominique
AU - Bourdon, Violaine
AU - Noguès, Catherine
AU - Noguchi, Tetsuro
AU - Popovici, Cornel
AU - Remenieras, Audrey
AU - Sobol, Hagay
AU - Coupier, Isabelle
AU - Pujol, Pascal
AU - Adenis, Claude
AU - Dumont, Aurélie
AU - Révillion, Françoise
AU - Muller, Danièle
AU - Barouk-Simonet, Emmanuelle
AU - Bonnet, Françoise
AU - Bubien, Virginie
AU - Longy, Michel
AU - Sevenet, Nicolas
AU - Gladieff, Laurence
AU - Guimbaud, Rosine
AU - Feillel, Viviane
AU - Toulas, Christine
AU - Dreyfus, Hélène
AU - Leroux, Christine Dominique
AU - Peysselon, Magalie
AU - Rebischung, Christine
AU - Legrand, Clémentine
AU - Baurand, Amandine
AU - Bertolone, Geoffrey
AU - Coron, Fanny
AU - Faivre, Laurence
AU - Jacquot, Caroline
AU - Lizard, Sarab
AU - Kientz, Caroline
AU - Lebrun, Marine
AU - Prieur, Fabienne
AU - Fert-Ferrer, Sandra
AU - Mari, Véronique
AU - Vénat-Bouvet, Laurence
AU - Bézieau, Stéphane
AU - Delnatte, Capucine
AU - Mortemousque, Isabelle
AU - Colas, Chrystelle
AU - Coulet, Florence
AU - Soubrier, Florent
AU - Warcoin, Mathilde
AU - Bronner, Myriam
AU - Sokolowska, Johanna
AU - Collonge-Rame, Marie Agnès
AU - Damette, Alexandre
AU - Gesta, Paul
AU - Lallaoui, Hakima
AU - Chiesa, Jean
AU - Molina-Gomes, Denise
AU - Ingster, Olivier
AU - Manouvrier-Hanu, Sylvie
AU - Lejeune, Sophie
AU - Giles, Graham G.
AU - Glendon, Gord
AU - Godwin, Andrew K.
AU - Goldberg, Mark S.
AU - Goldgar, David E.
AU - Guénel, Pascal
AU - Gutierrez-Barrera, Angelica M.
AU - Haeberle, Lothar
AU - Haiman, Christopher A.
AU - Håkansson, Niclas
AU - Hall, Per
AU - Hamann, Ute
AU - Harrington, Patricia A.
AU - Hein, Alexander
AU - Heyworth, Jane
AU - Hillemanns, Peter
AU - Hollestelle, Antoinette
AU - Hopper, John L.
AU - Hosgood, H. Dean
AU - Howell, Anthony
AU - Hu, Chunling
AU - Hulick, Peter J.
AU - Hunter, David J.
AU - Imyanitov, Evgeny N.
AU - Aghmesheh, Morteza
AU - Greening, Sian
AU - Amor, David
AU - Gattas, Mike
AU - Botes, Leon
AU - Buckley, Michael
AU - Friedlander, Michael
AU - Koehler, Jessica
AU - Meiser, Bettina
AU - Saleh, Mona
AU - Salisbury, Elizabeth
AU - Trainer, Alison
AU - Tucker, Kathy
AU - Antill, Yoland
AU - Dobrovic, Alexander
AU - Delatycki, Martin
AU - Hart, Stewart
AU - Nguyen-Dumont, Tu
AU - Southey, Melissa C.
AU - Milne, Roger L.
AU - ABCTB Investigators
AU - GEMO Study Collaborators
AU - kConFab
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074364016&partnerID=8YFLogxK
U2 - 10.1038/s41523-019-0127-5
DO - 10.1038/s41523-019-0127-5
M3 - Article
AN - SCOPUS:85074364016
SN - 2374-4677
VL - 5
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 38
ER -