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FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

About this Publication
Title
FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.
Pubmed ID
36707629 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Eur J Hum Genet. 2023 May; Volume 31 (Issue 5): Pages 578-587
Authors
Figlioli G, Billaud A, Ahearn TU, Antonenkova NN, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Blok MJ, Bogdanova NV, Bonanni B, Burwinkel B, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chanock SJ, NBCS Collaborators, Czene K, ...show more Devilee P, Dörk T, Engel C, Eriksson M, Fasching PA, Figueroa JD, Gabrielson M, Gago-Dominguez M, García-Closas M, González-Neira A, Grassmann F, Guénel P, Gündert M, Hadjisavvas A, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Hillemanns P, Hollestelle A, Hooning MJ, Hoppe R, Howell A, Humphreys K, KConFab Investigators, Jager A, Jakubowska A, Khusnutdinova EK, Ko YD, Kristensen VN, Lindblom A, Lissowska J, Lubiński J, Mannermaa A, Manoukian S, Margolin S, Mavroudis D, Newman WG, Obi N, Panayiotidis MI, Rashid MU, Rhenius V, Rookus MA, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Sironen R, Southey MC, Suvanto M, Tollenaar RAEM, Tomlinson I, Truong T, van der Kolk LE, van Veen EM, Wappenschmidt B, Yang XR, Bolla MK, Dennis J, Dunning AM, Easton DF, Lush M, Michailidou K, Pharoah PDP, Wang Q, Adank MA, Schmidt MK, Andrulis IL, Chang-Claude J, Nevanlinna H, Chenevix-Trench G, Evans DG, Milne RL, Radice P, Peterlongo P
Affiliations
  • IFOM ETS - The AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
  • N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
  • University Medical Center Hamburg-Eppendorf, Institute of Medical Biometry and Epidemiology, Hamburg, Germany.
  • University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
  • German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
  • Spanish National Cancer Research Centre (CNIO), Human Genetics Group, Madrid, Spain.
  • Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
  • Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands.
  • IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy.
...show more
  • German Cancer Research Center (DKFZ), Molecular Epidemiology Group, C080, Heidelberg, Germany.
  • University of Utah, Department of Internal Medicine and Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • University of Edinburgh, Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, Edinburgh, UK.
  • Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Oncology and Genetics Unit, Vigo, Spain.
  • Intermountain Healthcare, Salt Lake City, UT, USA.
  • Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
  • Leiden University Medical Center, Department of Pathology, Leiden, the Netherlands.
  • Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
  • University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany.
  • Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Santiago de Compostela, Spain.
  • Spanish National Cancer Research Centre (CNIO), Human Cancer Genetics Programme, Madrid, Spain.
  • INSERM, University Paris-Saclay, Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, Villejuif, France.
  • The Cyprus Institute of Neurology & Genetics, Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, Nicosia, Cyprus.
  • Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Familial Breast and Ovarian Cancer, Cologne, Germany.
  • German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Heidelberg, Germany.
  • University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK.
  • Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, the Netherlands.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • University of Manchester, Division of Cancer Sciences, Manchester, UK.
  • Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Center, Szczecin, Poland.
  • Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany.
  • Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
  • Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
  • M. Sklodowska-Curie National Research Oncology Institute, Department of Cancer Epidemiology and Prevention, Warsaw, Poland.
  • University of Eastern Finland, Translational Cancer Research Area, Kuopio, Finland.
  • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Unit of Medical Genetics, Department of Medical Oncology and Hematology, Milan, Italy.
  • Södersjukhuset, Department of Oncology, Stockholm, Sweden.
  • University Hospital of Heraklion, Department of Medical Oncology, Heraklion, Greece.
  • University of Manchester, Manchester Academic Health Science Centre, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester, UK.
  • The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Division of Psychosocial Research and Epidemiology, Amsterdam, the Netherlands.
  • University Hospital of Larissa, Department of Oncology, Larissa, Greece.
  • King's College London, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, London, UK.
  • Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, Victoria, Australia.
  • University of Helsinki, Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
  • Leiden University Medical Center, Department of Surgery, Leiden, the Netherlands.
  • The University of Edinburgh, Cancer Research Centre, Edinburgh, UK.
  • The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Family Cancer Clinic, Amsterdam, the Netherlands.
  • University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK.
  • Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, Ontario, Canada.
  • QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, Queensland, Australia.
  • Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Experimental Oncology, Milan, Italy.
  • IFOM ETS - The AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy. paolo.peterlongo@ifom.eu.
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.

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