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

Billaud A, Figlioli G, Mooser C, Casamassima I, Azzoni V, Srivatsa J, Colombo M, Caleca L, Ahearn TU, Andrulis IL, Antoniou AC, Beckmann M, Behrens S, Bermisheva M, Bogdanova NV, Bolla MK, Bonanni B, Brüning T, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Czene K, Dennis J, Devilee P, Dörk T, Dunning AM, Eriksson M, Evans DG, Fasching P, Figueroa JD, Gabrielson M, Gago-Dominguez M, González-Neira A, Guénel P, Hadjisavvas A, Hahnen E, Hamann U, Hillemanns P, Hollestelle A, Hooning MJ, Hoppe R, Howell A, Jakubowska A, Kristensen VN, Lubiński J, Lush M, Manoukian S, Mavroudis D, Milne RL, Mulligan AM, Newman WG, Obi N, Panayiotidis MI, Pita G, Rashid MU, Rhenius V, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Southey MC, Spurdle AB, Tomlinson I, Truong T, Wang Q, Wendt C, Auer PL, Boddicker NJ, Bodelon C, Burnside ES, Chen F, Couch FJ, Domchek SM, Eliassen HA, Haiman C, Hodge JM, Hu C, Huang H, Lindstrom S, Martinez ME, Nathanson KL, Neuhausen SL, O'Brien KM, Olson JE, Palmer JR, Patel AV, Ruddy KJ, Sandler DP, Teras LR, Weinberg CR, Weitzel JN, Winham SJ, Yadav S, Yao S, Zirpoli G, Janatova M, Kleibl Z, Kleiblova P, Soukupova J, Zhao Q, Devereux L, James PA, Campbell IG, Nguyen-Dumont T, Dowty JG, Andrieu N, Lesueur F, Stoppa-Lyonnet D, Hoya Mdl, Radice P, Sørensen CS, Peterlongo P (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 85

Article Number: 104619

DOI: 10.1016/j.breast.2025.104619

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.

Authors with CRIS profile

Involved external institutions

IFOM - FIRC Institute of Molecular Oncology Italy (IT) University of Copenhagen Denmark (DK) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Erasmus University Medical Center (MC) Netherlands (NL) Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Germany (DE) University of Manchester United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of Oslo Norway (NO) University of Cambridge United Kingdom (GB) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) University General Hospital of Heraklion Greece (GR) Cancer Council Victoria Australia (AU) University of Toronto Canada (CA) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Cyprus Institute of Neurology and Genetics Cyprus (CY) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) General University Hospital of Larissa Greece (GR) King’s College London United Kingdom (GB) Universitätsklinikum Köln Germany (DE) Mayo Clinic United States (USA) (US) American Cancer Society United States (USA) (US) University of Wisconsin - Madison United States (USA) (US) Keck School of Medicine of USC United States (USA) (US) University of Pennsylvania (UPenn) United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Lunenfeld-Tanenbaum Research Institute Canada (CA) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung, Institut der Ruhr-Universität Bochum (IPA) Germany (DE) University of Utah United States (USA) (US) University of Edinburgh United Kingdom (GB) Instituto de Investigación Sanitaria Galicia Sur Spain (ES) Intermountain Healthcare United States (USA) (US) Karolinska Institute Sweden (SE) Leiden University Medical Center Netherlands (NL) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP) France (FR) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Oxford United Kingdom (GB) Södersjukhuset Sweden (SE) Medical College of Wisconsin (MCW) United States (USA) (US) University of Kansas (KU) United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Boston University United States (USA) (US) General University Hospital in Prague / Všeobecná Fakultní Nemocnice v Praze (VFN) Czech Republic (CZ) Peter MacCallum Cancer Centre Australia (AU) The University of Melbourne Australia (AU) The University of Melbourne Australia (AU) Melbourne School of Population and Global Health Australia (AU) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Institut Curie France (FR) Hospital Clínico San Carlos Spain (ES) Harvard T.H. Chan School of Public Health United States (USA) (US) University of Washington United States (USA) (US) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) City of Hope Medical Center United States (USA) (US) National Institute of Environmental Health Sciences (NIEHS) United States (USA) (US)

How to cite

APA:

Billaud, A., Figlioli, G., Mooser, C., Casamassima, I., Azzoni, V., Srivatsa, J.,... Peterlongo, P. (2026). 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, 85. https://doi.org/10.1016/j.breast.2025.104619

MLA:

Billaud, Amandine, et al. "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 85 (2026).

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