| Title: |
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 |
| Authors: |
Billaud, Amandine; Figlioli, Gisella; Mooser, Clémence; Casamassima, Irene; Azzoni, Violette; Srivatsa, Jahnavi; Colombo, Mara; Caleca, Laura; Ahearn, Thomas, U; Andrulis, Irene, L; Antoniou, Antonis, C; Beckmann, Matthias, W; Behrens, Sabine; Bermisheva, Marina; Bogdanova, Natalia, V; Bolla, Manjeet, K; Bonanni, Bernardo; Brüning, Thomas; Camp, Nicola, J; Campbell, Archie; Castelao, Jose, E; Cessna, Melissa, H; Chang-Claude, Jenny; Czene, Kamila; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dunning, Alison, M; Eriksson, Mikael; Evans, D, Gareth; Fasching, Peter, A; Figueroa, Jonine, D; Gabrielson, Marike; Gago-Dominguez, Manuela; González-Neira, Anna; Guénel, Pascal; Hadjisavvas, Andreas; Hahnen, Eric; Hamann, Ute; Hillemanns, Peter; Hollestelle, Antoinette; Hooning, Maartje, J; Hoppe, Reiner; Howell, Anthony; Jakubowska, Anna; Kristensen, Vessela, N; Lubiński, Jan; Lush, Michael; Manoukian, Siranoush; Mavroudis, Dimitrios; Milne, Roger, L; Mulligan, Anna, Marie; Newman, William, G; Obi, Nadia; Panayiotidis, Mihalis, I; Pita, Guillermo; Rashid, Muhammad, U; Rhenius, Valerie; Saloustros, Emmanouil; Sawyer, Elinor, J; Schmutzler, Rita, K; Shah, Mitul; Southey, Melissa, C; Spurdle, Amanda, B; Tomlinson, Ian; Truong, Thérèse; Wang, Qin; Wendt, Camilla; Auer, Paul, L; Boddicker, Nicholas, J; Bodelon, Clara; Burnside, Elizabeth, S; Chen, Fei; Couch, Fergus, J; Domchek, Susan, M; Eliassen, Heather, A; Haiman, Christopher; Hodge, James, M; Hu, Chunling; Huang, Hongyan; Lindstrom, Sara; Martinez, Maria, Elena; Nathanson, Katherine, L; Neuhausen, Susan, L; O’brien, Katie, M; Olson, Janet, E; Palmer, Julie, R; Patel, Alpa, V; Ruddy, Kathryn, J; Sandler, Dale, P; Teras, Lauren, R; Weinberg, Clarice, R; Weitzel, Jeffrey, N; Winham, Stacey, J; Yadav, Siddhartha; Yao, Song; Zirpoli, Gary; Janatova, Marketa; Kleibl, Zdenek; Kleiblova, Petra; Soukupova, Jana; Zhao, Qihong; Devereux, Lisa; James, Paul, A; Campbell, Ian, G; Nguyen-Dumont, Tu; Dowty, James, G; Andrieu, Nadine; Lesueur, Fabienne; Stoppa-Lyonnet, Dominique; Hoya, Miguel, de La; Radice, Paolo; Sørensen, Claus, Storgaard; Peterlongo, Paolo |
| Contributors: |
Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA); Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE); Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ); Institut de Cancérologie de l'Ouest Angers/Nantes (UNICANCER/ICO); UNICANCER; Istituto Clinico Humanitas Milan (IRCCS Milan); Humanitas University Milan (Hunimed); Københavns Universitet = University of Copenhagen = Université de Copenhague (UCPH); Alma Mater Studiorum Università di Bologna = University of Bologna Bologne (UNIBO); National Institutes of Health Bethesda, MD, USA (NIH); University of Toronto; University of Cambridge Cambridge, UK (CAM); Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg (FAU); Universität Heidelberg Heidelberg = Heidelberg University; Institute of Biochemistry and Genetics of Ufa Scientific Centre; Russian Academy of Sciences Moscow (RAS); Medizinische Hochschule Hannover = Hannover Medical School (MHH); IRCCS Ospedale San Raffaele Milan, Italy; Ruhr University Bochum = Ruhr-Universität Bochum Bochum (RUB); University of Utah; The University of Edinburgh; Instituto de Investigación Sanitaria Galicia Sur Vigo, Spain; Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf Hamburg (UKE); Karolinska Institutet = Karolinska Institute Stockholm; Leiden University Medical Center Leiden (LUMC); Universiteit Leiden = Leiden University; Manchester University NHS Foundation Trust (MFT); University Hospital Erlangen = Uniklinikum Erlangen; Cancer Center Karolinska Karolinska Institutet (CCK); Complejo Hospitalario Universitario de Santiago de Compostela ESpaña = USC University Hospital Complex Spain = Centre hospitalier universitaire de Saint-Jacques-de-Compostelle Espagne (CHUS); CIBER de Enfermedades Raras (CIBERER); Centre de recherche en épidémiologie et santé des populations (CESP); Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse; AP-HP. Université Paris Saclay-AP-HP. Université Paris Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay; Mode de vie, génétique et santé : études intégratives et transgénérationnelles (U1018 (Équipe 9) - CESP); Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP); AP-HP. Université Paris Saclay-AP-HP. Université Paris Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse; Cyprus Institute of Neurology and Genetics; Universität zu Köln = University of Cologne; German Cancer Research Center - Deutsches Krebsforschungszentrum Heidelberg (DKFZ); Erasmus MC Cancer Institute, Rotterdam; Erasmus University Medical Center Rotterdam (Erasmus MC); Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology Stuttgart; Arizona State University Tempe (ASU); Pomeranian Medical University Szczecin (PUM); Oslo University Hospital Oslo; IRCCS Istituto Nazionale dei Tumori Milano; Monash university; Mississippi State University Mississippi; Spanish National Cancer Research Center (CNIO); University of Thessaly Lamia; King‘s College London; University Hospital of Cologne Cologne; University of Oxford; Institut Gustave Roussy (IGR); Medical College of Wisconsin Milwaukee (MCW); Mayo Clinic Rochester; American Cancer Society Atlanta, GA, USA; University of Wisconsin School of Medicine and Public Health; University of Wisconsin-Madison; Keck School of Medicine Los Angeles; University of Southern California (USC); Perelman School of Medicine; University of Pennsylvania Philadelphia; Harvard Medical School Boston (HMS); Harvard T.H. Chan School of Public Health; University of Washington Seattle; University of California (UC); Beckman Research Institute Duarte, CA; National Institute of Environmental Health Sciences Durham, NC, USA (NIEHS-NIH); Boston University Boston (BU); University of Kansas Kansas City; Roswell Park Cancer Institute Buffalo (RPCI); Univerzita Karlova Praha, Česká republika = Charles University Prague, Czech Republic = Université Charles Prague, Republique tchèque (UK); Peter MacCallum Cancer Centre; University of Melbourne; Institut Curie Paris; Oncologie Computationnelle (OC); Institut Curie Paris -Institut National de la Santé et de la Recherche Médicale (INSERM); Institut Curie, PSL Research University, INSERM U1339, CNRS UMR3666, Chemical Biology of Cancer Unit, Paris, France (Institut Curie - CBC); Instituto de Investigación Sanitaria del Hospital Clínico San Carlos Madrid, Spain (IdISSC); European Institute of Oncology Milan (ESMO) |
| Source: |
ISSN: 0960-9776 ; The Breast ; https://hal.science/hal-05464797 ; The Breast, 2026, 85, pp.104619. ⟨10.1016/j.breast.2025.104619⟩. |
| Publisher Information: |
CCSD; Elsevier |
| Publication Year: |
2026 |
| Collection: |
Université de Versailles Saint-Quentin-en-Yvelines: HAL-UVSQ |
| Subject Terms: |
Meta-analysis; Genetic predisposition; Gene editing; FANCM; CRISPR-Cas9; Breast cancer risk; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41223770; PUBMED: 41223770; PUBMEDCENTRAL: PMC12657754 |
| DOI: |
10.1016/j.breast.2025.104619 |
| Availability: |
https://hal.science/hal-05464797; https://hal.science/hal-05464797v1/document; https://hal.science/hal-05464797v1/file/1-s2.0-S0960977625006368-main.pdf; https://doi.org/10.1016/j.breast.2025.104619 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.92CF8822 |
| Database: |
BASE |