Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer

The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.

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Journal
The Breast
Published
2025-10-30
DOI
https://doi.org/10.1016/j.breast.2025.104619
Primary Topic
BRCA gene mutations in cancer
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article
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article

Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer

Lisa Devereux, Maria Elena Martinez, Marina Bermisheva, Chunling Hu et al.
The Breast
BRCA gene mutations in cancer
article

Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer

Lisa Devereux, Maria Elena Martinez, Marina Bermisheva, Chunling Hu, Gisella Figlioli, Zdeněk Kleibl, Guillermo Pita, Tú Nguyen‐Dumont, Jana Soukupová, Michael Lush, Markéta Janatová, Ian Tomlinson, A. Heather Eliassen, Natalia Bogdanova, Paul A. James, Alpa V. Patel, Melissa H. Cessna, Jose E. Castelao, Jenny Chang‐Claude, Manuela Gago-Domínguez, Thilo Dörk, Jonine D. Figueroa, Stacey J. Winham, Kathryn J. Ruddy, Hongyan Huang, Thérèse Truong, Jeffrey N. Weitzel, Joe Dennis, Claus Storgaard Sørensen, Thomas U. Ahearn, Vessela N. Kristensen, Archie Campbell, Siranoush Manoukian, Clara Bodelón, Pascal Guénel, Ian Campbell, Mikael Eriksson, Alison M. Dunning, Anna González‐Neira, Roger Laughlin Milne, Violette Azzoni, Petra Kleiblová, Muhammad Usman Rashid, James M. Hodge, Christopher Haiman, Peter Devilee, Marike Gabrielson, Amandine Billaud, Andreas Hadjisavvas, Sabine Behrens, Laura Caleca, Anna Marie Mulligan, Anna Jakubowska, Gary Zirpoli, Katie M. O’Brien, Anthony Howell, Dale P. Sandler, Emmanouil Saloustros, Elinor J. Sawyer, Mara Colombo, Nicola J. Camp, Maartje J. Hooning, Eric Hahnen, Katherine L. Nathanson, Catherine Mooser, William G. Newman, Mitul Shah, Valerie Rhenius, Siddhartha Yadav, Bernardo Bonanni, Nicholas Boddicker, Fabienne Lesueur, Elizabeth S. Burnside, Qihong Zhao, Irene Casamassima, D. Gareth Evans, Janet E. Olson, Nadine Andrieu, Melissa C. Southey, Julie R. Palmer, Fei Chen, Qin Wang, Song Yao, Paul L. Auer, Ute Hamann, Reiner Hoppe, Nadia Obi, Peter A. Fasching, Kamila Czene, Matthias W. Beckmann, Jan Lubiński, Paolo Peterlongo, Amanda B. Spurdle, Paolo Radice, Fergus J. Couch, Antonis C Antoniou, Peter Hillemanns, Miguel de la Hoya, Mihalis I. Panayiotidis, James G. Dowty, Sara Lindström, Susan M. Domchek, Irene L. Andrulis, Thomas Brüning, Susan L. Neuhausen, Dominique Stoppa-Lyonnet, Dimitrios Mavroudis, Antoinette Hollestelle, Lauren R. Teras, Manjeet K. Bolla, Rita K. Schmutzler, Camilla Wendt, Clarice Ring Weinberg, Jahnavi Srivatsa
article en

Abstract

The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.

The BreastVol. 85
Intermountain Healthcare (US), Boston University (US), University of Southern California (US), University of Copenhagen (DK), Oslo University Hospital (NO), Brigham and Women's Hospital (US), American Cancer Society (US), Roswell Park Comprehensive Cancer Center (US), Centre National de la Recherche Scientifique (FR), University Health Network (CA), Mayo Clinic (US), Humanitas University (IT), University of Wisconsin–Madison (US), Harvard University (US), University of Thessaly (GR), Inserm (FR), Universität Hamburg (DE), The University of Melbourne (AU), German Cancer Research Center (DE), University of Cologne (DE), King's College London (GB), University of Oslo (NO), Université de Versailles Saint-Quentin-en-Yvelines (FR), Cancer Council Victoria (AU), University of Washington (US), Medical College of Wisconsin (US), Université Paris Cité (FR), Lunenfeld-Tanenbaum Research Institute (CA), Charles University (CZ), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), Heidelberg University (DE), University of Cambridge (GB), Université Paris Sciences et Lettres (FR), Leiden University Medical Center (NL), Peter MacCallum Cancer Centre (AU), Huntsman Cancer Institute (US), University Hospital Heidelberg (DE), WinnMed (US), Edinburgh Cancer Research (GB), Karolinska Institutet (SE), Medizinische Hochschule Hannover (DE), University of California San Diego (US), University of Oxford (GB), St Mary's Hospital (GB), Universitätsklinikum Erlangen (DE), Spanish National Cancer Research Centre (ES), Galicia Sur Biomedical Foundation (ES), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR), Stockholm South General Hospital (SE), National Institute of Environmental Health Sciences (US), Complejo Hospitalario Universitario de Santiago (ES), The University of Kansas Cancer Center (US), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES), Centre de recherche en Epidémiologie et Santé des Populations (FR), Ufa Institute of Chemistry (RU), St Mary's Hospital (GB), University Medical Center Hamburg-Eppendorf (DE), City of Hope (US), Centre for Biomedical Network Research on Rare Diseases (ES), IFOM (IT), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Institute for Prevention and Occupational Medicine (DE), Monash Health (AU), Fundación Pública Galega de Medicina Xenómica (ES), University Cancer Center Hamburg (DE), Shaukat Khanum Memorial Cancer Hospital and Research Center (PK), University Hospital of Heraklion (GR), Institut Cochin (FR), Mayo Clinic in Florida (US), Instituto de Investigación Sanitaria de Santiago (ES), Comprehensive Cancer Center Erlangen (DE), Erasmus MC Cancer Institute (NL), University Hospital Cologne (DE), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Servicio Gallego de Salud (ES), International Hereditary Cancer Center (PL), General University Hospital in Prague (CZ), IRCCS Humanitas Research Hospital (IT), Department of Health and Human Services (US), Beckman Research Institute, Université d'Angers (FR), Cyprus Institute of Neurology and Genetics (CY), Monash University (AU), Seattle University (US), European Institute of Oncology (IT), University of Pennsylvania (US), Pomeranian Medical University (PL), Institut Curie (FR), University of Bologna (IT)
U.S. Department of Health and Human Services, American Cancer Society, Susan G. Komen for the Cure, Breast Cancer Research Foundation, University of Pennsylvania, University of Wisconsin-Madison, Division of Cancer Prevention, National Cancer Institute, University of Utah, Itä-Suomen Yliopisto, Deutsches Krebsforschungszentrum, Kreftforeningen, Genome Canada, Wellcome Trust, Huntsman Cancer Institute, Scottish Government, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Fondation du cancer du sein du Québec, Government of Canada, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Scottish Funding Council, University of Cambridge, King's College London, European Commission, National Breast Cancer Foundation, Cancer Australia, Cancer Institute NSW, Agency for Science, Technology and Research, Robert Bosch Stiftung, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Research Promotion Foundation, Bundesministerium für Bildung und Forschung, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Ministerio de Economía y Competitividad, Deutsche Gesetzliche Unfallversicherung, Ministerio de Sanidad, Servicios Sociales e Igualdad, Karolinska Institutet, Kuopion Yliopistollinen Sairaala, University of Crete, Fondation de France, KWF Kankerbestrijding, Fondazione Umberto Veronesi, Associazione Italiana per la Ricerca sul Cancro, Medizinischen Hochschule Hannover, Deutsche Krebshilfe, Institut National Du Cancer, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, Xunta de Galicia, Ministry of Science and Higher Education of the Russian Federation, Freistaat Sachsen, National Institutes of Health, U.S. Army, Chief Scientist Office, Scottish Government Health and Social Care Directorate, Manchester Biomedical Research Centre, Canadian Institutes of Health Research, Medical Research Council, National Health and Medical Research Council, Cancer Council South Australia, Cancer Council Victoria, Cancer Council NSW, Cancer Council Tasmania, Instituto de Salud Carlos III, Programme Grants for Applied Research, European Regional Development Fund, Servicio Gallego de Salud, NIHR Cambridge Biomedical Research Centre, National Cancer Institute, Division of Graduate Education, Medical Research and Materiel Command
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BRCA gene mutations in cancer
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