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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 A, Figlioli G, Mooser C, Casamassima I, Azzoni V, Srivatsa J, Colombo M, Caleca L, Ahearn TU, Andrulis IL, Antoniou AC, Beckmann MW, Behrens S, Bermisheva M, Bogdanova NV, Bolla MK, Bonanni B, Brüning T, Camp NJ, Campbell A, ...show more Castelao JE, Cessna MH, Chang-Claude J, NBCS Collaborators, Czene K, Dennis J, Devilee P, Dörk T, Dunning AM, Eriksson M, Evans DG, Fasching PA, 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, kConFab Investigators, 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, CZECANCA consortium, Zhao Q, Devereux L, James PA, Campbell IG, Nguyen-Dumont T, Dowty JG, Andrieu N, Lesueur F, Stoppa-Lyonnet D, GENESIS, Hoya M, Radice P, Sørensen CS, Peterlongo P

Affiliations

  • Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy; Unité de Génomique Fonctionnelle, Institut de Cancérologie de l'Ouest Nantes-Angers, Angers, France; Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, Angers, France.
  • Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
  • Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy.
  • Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy.
  • Unit of Predictive Medicine, Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda MD, USA.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
...show more
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
  • Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
  • IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy.
  • Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
  • Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK.
  • Oncólogy and Genétics Group, Instituto Investigación Sanitaria Galicia Sur-SERGAS, Vigo, Spain.
  • Intermountain Healthcare, Salt Lake City, UT, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Research, Vestre Viken Hospital, Drammen, Norway; Section for Breast- and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Ullevål, Oslo, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway; Department of Pathology, Akershus University Hospital, Lørenskog, Norway; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, Oslo, Norway; National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, Oslo, Norway; Department of Oncology, Akershus University Hospital, Lørenskog, Norway; Oslo Breast Cancer Research Consortium, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center Lower Saxony, Hannover Medical School, Hannover, Germany.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda MD, USA; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
  • Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
  • Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
  • Team "Exposome and Heredity", CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
  • Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany.
  • Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Research Department, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
  • Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
  • Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
  • Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
  • Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
  • Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute for Occupational and Maritime Medicine (ZfAM), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus; Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, Mississippi, USA.
  • Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
  • Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
  • School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia.
  • Public Health Program, QIMR Berghofer, Brisbane, Queensland, Australia.
  • Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford, UK.
  • Department of Oncology, Södersjukhuset, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
  • Division of Biostatistics, Data Science Institute, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA.
  • Department of Population Science, American Cancer Society, Atlanta, USA.
  • Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, USA.
  • Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, USA.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
  • Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
  • Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
  • Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA.
  • University of Washington, Seattle, USA.
  • University of California, San Diego, La Jolla California, USA.
  • Beckman Research Institute of City of Hope, Duarte, USA.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham NC, USA.
  • Mayo Clinic, Rochester, USA.
  • Slone Epidemiology Center, Boston University Chobanian & Avedisian School of Medicine, Boston, USA.
  • Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Durham NC, USA.
  • The University of Kansas Cancer Center, Kansas City, KS USA.
  • Department of Medical Oncology, Mayo Clinic, Rochester, USA.
  • Roswell Park Cancer Center, Buffalo, USA.
  • Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
  • Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia; Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.
  • Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia; Clinical Genomics, School of Translational Medicine, Monash University, Melbourne, Australia.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Inserm, U1331, Paris, France; Institut Curie, Paris, France; Mines Paris, Fontainebleau, France; PSL Research University, Paris, France.
  • Institut Curie, Service de Génétique, Paris, France; Inserm, U1339, Paris, France; Université Paris Cité, Paris, France.
  • Inserm, U1331, Paris, France; Institut Curie, Paris, France; Mines Paris, Fontainebleau, France; PSL Research University, Paris, France; Institut Curie, Service de Génétique, Paris, France; Inserm, U1339, Paris, France; Université Paris Cité, Paris, France.
  • Molecular Oncology Laboratory, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
  • Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy. Electronic address: paolo.peterlongo@ieo.it.

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.

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Publication Details

PubMed ID
41223770

Digital Object Identifier
10.1016/j.breast.2025.104619

Publication
Breast. 2026 Feb; Volume 85: Pages 104619

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