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 N. Antonenkova, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Marinus J. Blok, Natalia V. Bogdanova, Bernardo Bonanni, Barbara Burwinkel, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Melissa H. Cessna, Stephen J. Chanock, Kamila Czene, Peter DevileeThilo Dörk, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Jonine D. Figueroa, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Anna González-Neira, Felix Grassmann, Pascal Guénel, Melanie Gündert, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Patricia A. Harrington, Wei He, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, Agnes Jager, Anna Jakubowska, Elza K. Khusnutdinova, Yon Dschun Ko, Vessela N. Kristensen, Annika Lindblom, Jolanta Lissowska, Jan Lubiński, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, William G. Newman, Nadia Obi, Mihalis I. Panayiotidis, Muhammad U. Rashid, Valerie Rhenius, Matti A. Rookus, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Reijo Sironen, Melissa C. Southey, Maija Suvanto, Rob A.E.M. Tollenaar, Ian Tomlinson, Thérèse Truong, Lizet E. van der Kolk, Elke M. van Veen, Barbara Wappenschmidt, Xiaohong R. Yang, Manjeet K. Bolla, Joe Dennis, Alison M. Dunning, Douglas F. Easton, Michael Lush, Kyriaki Michailidou, Paul D.P. Pharoah, Qin Wang, Muriel A. Adank, Marjanka K. Schmidt, Irene L. Andrulis, Jenny Chang-Claude, Heli Nevanlinna, Georgia Chenevix-Trench, D. Gareth Evans, Roger L. Milne, Paolo Radice, Paolo Peterlongo, NBCS Collaborators, kConFab Investigators

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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.

Original languageEnglish
Pages (from-to)578-587
Number of pages10
JournalEuropean Journal of Human Genetics
Volume31
Issue number5
DOIs
Publication statusPublished - 1 May 2023

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