FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women
Gisella Figlioli, Amandine Billaud, Thomas U. Ahearn, Natalia Antonenkova, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benı́tez, Marina Bermisheva, Marinus J. Blok, Natalia Bogdanova, Bernardo Bonanni, Barbara Burwinkel, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Melissa H. Cessna, Stephen J. Chanock, NBCS Collaborators, Kristine Kleivi Sahlberg, Anne‐Lise Børresen‐Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, OSBREAC, Tone F. Bathen, Elin Borgen, Britt Fritzman, Øystein Garred, Gry Aarum Geitvik, Solveig Hofvind, Anita Langerød, Ole Christian Lingjærde, Gunhild M. Mælandsmo, Hege G. Russnes, Helle Kristine Skjerven, Thérese Sørlie, Grethe I.G. Alnæs, Kamila Czene, Peter Devilee, Thilo Dörk, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Jonine D. Figueroa, Marike Gabrielson, Manuela Gago-Domínguez, Montserrat García‐Closas, Anna González‐Neira, Felix Graßmann, Pascal Guénel, Melanie Gündert, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Patricia Harrington, Wei He, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, KConFab Investigators, David J. Amor, Lesley Andrews, Yoland Antill, Rosemary L. Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa A. Brown, Michael F. Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Alice Christian, Paul A. Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret C. Cummings, Sarah‐Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey L. Edwards
Abstract
Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.