The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Creators: name: Figlioli, Gisella
name: Bogliolo, Massimo
name: Catucci, Irene
name: Caleca, Laura
name: Lasheras, Sandra Viz
name: Pujol, Roser
name: Kiiski, Johanna I.
name: Muranen, Taru A.
name: Barnes, Daniel R.
name: Dennis, Joe
name: Michailidou, Kyriaki
name: Bolla, Manjeet K.
name: Leslie, Goska
name: Aalfs, Cora M.
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name: Adlard, Julian
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name: Cadoo, Karen
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name: Ahearn, Thomas
name: Aittomäki, Kristiina
name: Ambrosone, Christine B.
name: Andrews, Lesley
name: Anton-Culver, Hoda
name: Antonenkova, Natalia N.
name: Arndt, Volker
name: Arnold, Norbert
name: Aronson, Kristan J.
name: Arun, Banu K.
name: Asseryanis, Ella
name: Auber, Bernd
name: Auvinen, Päivi
name: Azzollini, Jacopo
name: Balmaña, Judith
name: Barkardottir, Rosa B.
name: Barrowdale, Daniel
name: Barwell, Julian
name: Beane Freeman, Laura E.
name: Beauparlant, Charles Joly
name: Beckmann, Matthias W.
name: Behrens, Sabine
name: Benitez, Javier
name: Berger, Raanan
name: Bermisheva, Marina
name: Blanco, Amie M.
name: Blomqvist, Carl
name: Bogdanova, Natalia V.
name: Bojesen, Anders
name: Bojesen, Stig E.
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name: Brüning, Thomas
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name: Campa, Daniele
name: Campbell, Ian G.
name: Canzian, Federico
name: Castelao, Jose E.
name: Chang-Claude, Jenny
name: Chanock, Stephen J.
name: Claes, Kathleen B. M.
name: Clarke, Christine L.
name: Collavoli, Anita
name: Conner, Thomas A.
name: Cox, David G.
name: Cybulski, Cezary
name: Czene, Kamila
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name: Diez, Orland
name: Ding, Yuan Chun
name: Dite, Gillian S.
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name: Dos-Santos-Silva, Isabel
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name: Dwek, Miriam
name: Eccles, Diana M.
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name: Jones, Michael E.
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name: Lu, Karen H.
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name: Meindl, Alfons
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name: Miller, Austin
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name: Nathanson, Katherine L.
name: Neuhausen, Susan L.
name: Newman, William G.
name: Nguyen-Dumont, Tu
name: Nielsen, Finn Cilius
name: Nielsen, Sarah
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name: Offit, Kenneth
name: Olah, Edith
name: Olopade, Olufunmilayo I.
name: Olshan, Andrew F.
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name: Lindeman, Geoff
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name: Sexton, Adrienne
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name: Taylor, Jessica
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name: French, Juliet
name: Edwards, Stacey
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name: Patterson, Briony
name: Butow, Phyllis
name: Culling, Bronwyn
name: Caldon, Liz
name: Callen, David
name: Chauhan, Deepa
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name: Heiniger, Louise
name: Chauhan, Manisha
name: Christian, Alice
name: Dixon, Joanne
name: Kidd, Alexa
name: Cohen, Paul
name: Colley, Alison
name: Fenton, Georgina
name: Crook, Ashley
name: Dickson, Rebecca
name: Field, Michael
name: Cui, James
name: Cummings, Margaret
name: Dawson, Sarah-Jane
name: DeFazio, Anna
name: Delatycki, Martin
name: Dudding, Tracy
name: Edkins, Ted
name: Farshid, Gelareh
name: Flanagan, James
name: Fong, Peter
name: Forrest, Laura
name: Gallego-Ortega, David
name: George, Peter
name: Gill, Grantley
name: Kollias, James
name: Haan, Eric
name: Hart, Stewart
name: Jenkins, Mark
name: Hunt, Clare
name: Lakhani, Sunil
name: Lipton, Lara
name: Lobb, Liz
name: Mann, Graham
name: McLachlan, Sue Anne
name: O’Connell, Shona
name: O’Sullivan, Sarah
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name: Robinson, Bridget
name: Saunus, Jodi
name: Scott, Elizabeth
name: Shelling, Andrew
name: Williams, Rachael
name: Young, Mary Ann
Publisher: name: Apollo - University of Cambridge Repository
Year: 2019
Subjects: Article
/631/208/68
/692/4028/67/68
/631/67/68
article

description: 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.