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

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

NPJ breast cancer (2019-11-09)
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, Muriel A Adank, Julian Adlard, Simona Agata, Karen Cadoo, Bjarni A Agnarsson, Thomas 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
PMID31700994
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.