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E. M., 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 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 ORCID: 0000-0002-1878-2587, Doerk, Thilo, Schmidt, Marjanka K., Easton, Douglas F., Radice, Paolo ORCID: 0000-0001-6298-4111, Hahnen, Eric, Antoniou, Antonis C., Couch, Fergus J., Nevanlinna, Heli, Surralles, Jordi, Peterlongo, Paolo ORCID: 0000-0001-6951-6855, 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 ORCID: 0000-0002-2806-2401, Zeps, Nikolajs ORCID: 0000-0002-6404-6839, Belotti, Muriel, Bertrand, Ophelie, Birot, Anne-Marie, Buecher, Bruno, Caputo, Sandrine ORCID: 0000-0001-5338-9388, 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 ORCID: 0000-0002-4915-2254, Saunders, Christobel ORCID: 0000-0003-2281-9829, 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 ORCID: 0000-0002-4860-9232, Colley, Alison, Fenton, Georgina, Crook, Ashley ORCID: 0000-0001-5578-0460, Dickson, Rebecca, Field, Michael, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dudding, Tracy, Edkins, Ted, Farshid, Gelareh, Flanagan, James ORCID: 0000-0003-4955-1383, 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 and Young, Mary Ann (2019). The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. npj Breast Cancer, 5. LONDON: NATURE PUBLISHING GROUP. ISSN 2374-4677

Full text not available from this repository.

Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, 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 pArg1931* 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Figlioli, GisellaUNSPECIFIEDorcid.org/0000-0002-0740-1363UNSPECIFIED
Bogliolo, MassimoUNSPECIFIEDorcid.org/0000-0001-8240-7784UNSPECIFIED
Catucci, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Barnes, Daniel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Freeman, Laura E. BeaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Crook, AshleyUNSPECIFIEDorcid.org/0000-0001-5578-0460UNSPECIFIED
Dickson, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Field, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cui, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cummings, MargaretUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dawson, Sarah-JaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeFazio, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delatycki, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dudding, TracyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edkins, TedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farshid, GelarehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flanagan, JamesUNSPECIFIEDorcid.org/0000-0003-4955-1383UNSPECIFIED
Fong, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forrest, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallego-Ortega, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
George, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gill, GrantleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kollias, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haan, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hart, StewartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jenkins, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunt, ClareUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lakhani, SunilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lipton, LaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lobb, LizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mann, GrahamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McLachlan, Sue AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Connell, ShonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Sullivan, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pieper, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robinson, BridgetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saunus, JodiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, ElizabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shelling, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Williams, RachaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, Mary AnnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-129513
DOI: 10.1038/s41523-019-0127-5
Journal or Publication Title: npj Breast Cancer
Volume: 5
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2374-4677
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FANCONI-ANEMIA; GENE; C.5791C-GREATER-THAN-T; MUTATIONSMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12951

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