Skip to Main Content

An official website of the United States government

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

About this Publication
Title
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.
Pubmed ID
31700994 (View this publication on the PubMed website)
Digital Object Identifier
Publication
NPJ Breast Cancer. 2019; Volume 5: Pages 38
Authors
Figlioli G, Bogliolo M, Catucci I, Caleca L, Lasheras SV, Pujol R, Kiiski JI, Muranen TA, Barnes DR, Dennis J, Michailidou K, Bolla MK, Leslie G, Aalfs CM, ABCTB Investigators, Adank MA, Adlard J, Agata S, Cadoo K, Agnarsson BA, ...show more Ahearn T, Aittomäki K, Ambrosone CB, Andrews L, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Arun BK, Asseryanis E, Auber B, Auvinen P, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Barwell J, Beane Freeman LE, Beauparlant CJ, Beckmann MW, Behrens S, Benitez J, Berger R, Bermisheva M, Blanco AM, Blomqvist C, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Borg A, Brady AF, Brauch H, Brenner H, Brüning T, Burwinkel B, Buys SS, Caldés T, Caliebe A, Caligo MA, Campa D, Campbell IG, Canzian F, Castelao JE, Chang-Claude J, Chanock SJ, Claes KBM, Clarke CL, Collavoli A, Conner TA, Cox DG, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Ditsch N, Domchek SM, Dorfling CM, Dos-Santos-Silva I, Durda K, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Eriksson M, Evans DG, Fasching PA, Figueroa J, Flyger H, Foulkes WD, Friebel TM, Friedman E, Gabrielson M, Gaddam P, Gago-Dominguez M, Gao C, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, GEMO Study Collaborators, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, Guénel P, Gutierrez-Barrera AM, Haeberle L, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hein A, Heyworth J, Hillemanns P, Hollestelle A, Hopper JL, Hosgood HD, Howell A, Hu C, Hulick PJ, Hunter DJ, Imyanitov EN, KConFab, Isaacs C, Jakimovska M, Jakubowska A, James P, Janavicius R, Janni W, John EM, Jones ME, Jung A, Kaaks R, Karlan BY, Khusnutdinova E, Kitahara CM, Konstantopoulou I, Koutros S, Kraft P, Lambrechts D, Lazaro C, Le Marchand L, Lester J, Lesueur F, Lilyquist J, Loud JT, Lu KH, Luben RN, Lubinski J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martens JWM, Maurer T, Mavroudis D, Mebirouk N, Meindl A, Menon U, Miller A, Montagna M, Nathanson KL, Neuhausen SL, Newman WG, Nguyen-Dumont T, Nielsen FC, Nielsen S, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Olshan AF, Olson JE, Olsson H, Osorio A, Ottini L, Peissel B, Peixoto A, Peto J, Plaseska-Karanfilska D, Pocza T, Presneau N, Pujana MA, Punie K, Rack B, Rantala J, Rashid MU, Rau-Murthy R, Rennert G, Lejbkowicz F, Rhenius V, Romero A, Rookus MA, Ross EA, Rossing M, Rudaitis V, Ruebner M, Saloustros E, Sanden K, Santamariña M, Scheuner MT, Schmutzler RK, Schneider M, Scott C, Senter L, Shah M, Sharma P, Shu XO, Simard J, Singer CF, Sohn C, Soucy P, Southey MC, Spinelli JJ, Steele L, Stoppa-Lyonnet D, Tapper WJ, Teixeira MR, Terry MB, Thomassen M, Thompson J, Thull DL, Tischkowitz M, Tollenaar RAEM, Torres D, Troester MA, Truong T, Tung N, Untch M, Vachon CM, van Rensburg EJ, van Veen EM, Vega A, Viel A, Wappenschmidt B, Weitzel JN, Wendt C, Wieme G, Wolk A, Yang XR, Zheng W, Ziogas A, Zorn KK, Dunning AM, Lush M, Wang Q, McGuffog L, Parsons MT, Pharoah PDP, Fostira F, Toland AE, Andrulis IL, Ramus SJ, Swerdlow AJ, Greene MH, Chung WK, Milne RL, Chenevix-Trench G, Dörk T, Schmidt MK, Easton DF, Radice P, Hahnen E, Antoniou AC, Couch FJ, Nevanlinna H, Surrallés J, Peterlongo P
Affiliations
  • IFOM - the FIRC Institute for Molecular Oncology, Genome Diagnostics Program, Milan, Italy.
  • 2Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona Spain.
  • Fondazione IRCCS Istituto Nazionale dei Tumori, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Milan, Italy.
  • University of Helsinki, Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
  • 7University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK.
  • 9Amsterdam UMC, lokatie AMC, Department of Clinical Genetics, Amsterdam, The Netherlands.
  • The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Family Cancer Clinic, Amsterdam, The Netherlands.
  • Chapel Allerton Hospital, Yorkshire Regional Genetics Service, Leeds, UK.
  • Veneto Institute of Oncology IOV - IRCCS, Immunology and Molecular Oncology Unit, Padua, Italy.
  • Memorial Sloan-Kettering Cancer Center, Department of Medicine, New York, NY USA.
...show more
  • Landspitali University Hospital, Department of Pathology, Reykjavik, Iceland.
  • 16National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, Bethesda, MD USA.
  • 17University of Helsinki, Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.
  • 18Roswell Park Cancer Institute, Buffalo, NY USA.
  • Nelune Comprehensive Cancer Care Centre, The Bright Alliance Building, Randwick, NSW Australia.
  • 20University of California Irvine, Department of Epidemiology, Genetic Epidemiology Research Institute, Irvine, CA USA.
  • N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
  • German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany.
  • University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Department of Gynaecology and Obstetrics, and Institute of Clinical Molecular Biology, Kiel, Germany.
  • Queen's University, Department of Public Health Sciences, and Cancer Research Institute, Kingston, ON Canada.
  • 25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.
  • 26Medical University of Vienna, Dept of OB/GYN and Comprehensive Cancer Center, Vienna, Austria.
  • 27Hannover Medical School, Institute of Human Genetics, Hannover, Germany.
  • 28Kuopio University Hospital, Cancer Center, Kuopio, Finland.
  • 31Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Department of Medical Oncology and Hematology, Unit of Medical Genetics, Milan, Italy.
  • 32Vall d'Hebron Institute of Oncology, High Risk and Cancer Prevention Group, Barcelona, Spain.
  • 35University Hospitals of Leicester NHS Trust, Leicestershire Clinical Genetics Service, Leicester, UK.
  • 36Centre Hospitalier Universitaire de Québec - Université Laval, Research Center, Genomics Center, Québec City, QC Canada.
  • University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, Erlangen, Germany.
  • German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
  • Spanish National Cancer Research Centre (CNIO), Human Genetics Group, Human Cancer Genetics Programme, Madrid, Spain.
  • Chaim Sheba Medical Center, The Institute of Oncology, Ramat Gan, Israel.
  • 43Ufa Federal Research Center of the Russian Academy of Sciences, Institute of Biochemistry and Genetics, Ufa, Russia.
  • 44University of California San Francisco, Cancer Genetics and Prevention Program, San Francisco, CA USA.
  • University of Helsinki, Department of Oncology, Helsinki University Hospital, Helsinki, Finland.
  • 49Aarhus University Hospital, Department of Clinical Genetics, Aarhus, Denmark.
  • Copenhagen University Hospital, Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark.
  • 53IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy.
  • 54Lund University and Skåne University Hospital, Department of Oncology, Lund, Sweden.
  • 55London North West University Hospitals NHS Trust, Northwick Park Hospital, North West Thames Regional Genetics Service, Kennedy Galton Centre, Harrow, UK.
  • 56Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • 60Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
  • 61German Cancer Research Center (DKFZ), Molecular Epidemiology Group, C080 Heidelberg, Germany.
  • 63Huntsman Cancer Institute, Department of Medicine, Salt Lake City, UT USA.
  • 64Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.
  • University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Institute of Human Genetics, Kiel, Germany.
  • 66University Hospital of Pisa, Section of Molecular Genetics, Dept. of Laboratory Medicine, Pisa, Italy.
  • 68Peter MacCallum Cancer Center, Research Division, Melbourne, VIC Australia.
  • 70German Cancer Research Center (DKFZ), Genomic Epidemiology Group, Heidelberg, Germany.
  • Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Oncology and Genetics Unit, Vigo, Spain.
  • 73Ghent University, Centre for Medical Genetics, Gent, Belgium.
  • 74University of Sydney, Westmead Institute for Medical Research, Sydney, NSW Australia.
  • University and University Hospital of Pisa, Section of Genetic Oncology, Dept. of Laboratory Medicine, Pisa, Italy.
  • 76Huntsman Cancer Institute, Salt Lake City, UT USA.
  • 77Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK.
  • 79Pomeranian Medical University, Department of Genetics and Pathology, Szczecin, Poland.
  • 80Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
  • 81Fox Chase Cancer Center, Department of Clinical Genetics, Philadelphia, PA USA.
  • 82Leiden University Medical Center, Department of Pathology, Leiden, The Netherlands.
  • 84Vall d'Hebron Institute of Oncology (VHIO), Oncogenetics Group, Barcelona, Spain.
  • 86Beckman Research Institute of City of Hope, Department of Population Sciences, Duarte, CA USA.
  • 87The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Victoria, Australia.
  • 88Ludwig Maximilian University of Munich, Department of Gynecology and Obstetrics, Munich, Germany.
  • Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Abramson Cancer Center, Philadelphia, PA USA.
  • 90University of Pretoria, Department of Genetics, Arcadia, South Africa.
  • 91London School of Hygiene and Tropical Medicine, Department of Non-Communicable Disease Epidemiology, London, UK.
  • 92University of Westminster, Department of Biomedical Sciences, Faculty of Science and Technology, London, UK.
  • 93University of Southampton, Cancer Sciences Academic Unit, Faculty of Medicine, Southampton, UK.
  • Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany.
  • 95Harvard Medical School, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA USA.
  • 97Lund University, Department of Cancer Epidemiology, Clinical Sciences, Lund, Sweden.
  • 98University of Manchester, Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester, UK.
  • Copenhagen University Hospital, Department of Breast Surgery, Herlev and Gentofte Hospital, Herlev, Denmark.
  • 104McGill University, Program in Cancer Genetics, Departments of Human Genetics and Oncology, Montréal, QC Canada.
  • 105Harvard T.H. Chan School of Public Health, Boston, MA USA.
  • 107Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Ramat Gan, Israel.
  • 109Memorial Sloan-Kettering Cancer Center, Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, New York, NY USA.
  • 110Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Genomic Medicine Group, Galician Foundation of Genomic Medicine, Santiago de Compostela, Spain.
  • 112Harvard T.H. Chan School of Public Health, Program in Genetic Epidemiology and Statistical Genetics, Boston, MA USA.
  • 113American Cancer Society, Epidemiology Research Program, Atlanta, GA USA.
  • Dana-Farber Cancer Institute, Cancer Risk and Prevention Clinic, Boston, MA USA.
  • 116Cedars-Sinai Medical Center, The Center for Bioinformatics and Functional Genomics at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA USA.
  • 119Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON Canada.
  • 120Kansas University Medical Center, Department of Pathology and Laboratory Medicine, Kansas City, KS USA.
  • 121McGill University, Department of Medicine, Montréal, QC Canada.
  • 123Huntsman Cancer Institute, University of Utah School of Medicine, Department of Dermatology, Salt Lake City, UT USA.
  • 124INSERM, University Paris-Sud, University Paris-Saclay, Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), Villejuif, France.
  • 125University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology and Clinical Genetics Program, Houston, TX USA.
  • 126Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Department of Gynaecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany.
  • 127University of Southern California, Department of Preventive Medicine, Keck School of Medicine, Los Angeles, CA USA.
  • 128Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden.
  • German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Heidelberg, Germany.
  • 131University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK.
  • 132The University of Western Australia, School of Population and Global Health, Perth, WA Australia.
  • Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
  • 133Erasmus MC Cancer Institute, Department of Medical Oncology, Family Cancer Clinic, Rotterdam, The Netherlands.
  • 134Albert Einstein College of Medicine, Department of Epidemiology and Public Health, Bronx, NY USA.
  • 135University of Manchester, Division of Cancer Sciences, Manchester, UK.
  • 136Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN USA.
  • 137NorthShore University HealthSystem, Center for Medical Genetics, Evanston, IL USA.
  • 96Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA USA.
  • 140N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
  • 141Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA.
  • 142Macedonian Academy of Sciences and Arts, Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Skopje, Republic of Macedonia.
  • 69The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC Australia.
  • 145Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Vilnius, Lithuania.
  • 147University Hospital Ulm, Department of Gynaecology and Obstetrics, Ulm, Germany.
  • 148Stanford University School of Medicine, Department of Medicine (Oncology) and Stanford Cancer Institute, Stanford, CA USA.
  • 115The Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK.
  • 149Cedars-Sinai Medical Center, Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA USA.
  • 151National Cancer Institute, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD USA.
  • 152National Centre for Scientific Research 'Demokritos', Molecular Diagnostics Laboratory, INRASTES, Athens, Greece.
  • 153VIB, VIB Center for Cancer Biology, Leuven, Belgium.
  • IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONC, Molecular Diagnostic Unit, Hereditary Cancer Program, Barcelona, Spain.
  • 156University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI USA.
  • Inserm U900, Genetic Epidemiology of Cancer team, Paris, France.
  • 161Mayo Clinic, Department of Health Sciences Research, Rochester, MN USA.
  • 162National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD USA.
  • 163University of Texas MD Anderson Cancer Center, Department of Gynecologic Oncology and Clinical Cancer Genetics Program, Houston, TX USA.
  • 164University of Cambridge, Clinical Gerontology, Department of Public Health and Primary Care, Cambridge, UK.
  • 30University of Eastern Finland, Translational Cancer Research Area, Kuopio, Finland.
  • 129Södersjukhuset, Department of Oncology, Stockholm, Sweden.
  • 72University Medical Center Hamburg-Eppendorf, Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), Hamburg, Germany.
  • 168University Hospital of Heraklion, Department of Medical Oncology, Heraklion, Greece.
  • University College London, MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London, UK.
  • Roswell Park Cancer Institute, NRG Oncology, Clinical Trials Development Division, Buffalo, NY USA.
  • 171Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, VIC Australia.
  • Rigshospitalet, Copenhagen University Hospital, Center for Genomic Medicine, Copenhagen, Denmark.
  • The University of Chicago, Center for Clinical Cancer Genetics, Chicago, IL USA.
  • 174Latvian Biomedical Research and Study Centre, Riga, Latvia.
  • 176National Institute of Oncology, Department of Molecular Genetics, Budapest, Hungary.
  • 177University of North Carolina at Chapel Hill, Department of Epidemiology, Lineberger Comprehensive Cancer Center, Chapel Hill, NC USA.
  • 178University La Sapienza, Department of Molecular Medicine, Rome, Italy.
  • 179Portuguese Oncology Institute, Department of Genetics, Porto, Portugal.
  • IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONC, ProCURE, Oncobell, Barcelona, Spain.
  • 181Leuven Cancer Institute, University Hospitals Leuven, Multidisciplinary Breast Center, Department of General Medical Oncology, Leuven, Belgium.
  • 182Karolinska Institutet, Clinical Genetics, Stockholm, Sweden.
  • 175Memorial Sloan-Kettering Cancer Center, Clinical Genetics Service, Department of Medicine, New York, NY USA.
  • 184Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel.
  • 185Hospital Universitario Puerta de Hierro, Medical Oncology Department, Madrid, Spain.
  • 186The Netherlands Cancer Institute, Department of Epidemiology, Amsterdam, The Netherlands.
  • 187Fox Chase Cancer Center, Biostatistics and Bioinformatics Facility, Philadelphia, PA USA.
  • 188Vilnius University, Medical Faculty, Institute of Clinical Medicine, Vilnius, Lithuania.
  • 189University Hospital of Larissa, Department of Oncology, Larissa, Greece.
  • 190University of Wisconsin, Cancer Center at ProHealth Care, Waukesha, WI USA.
  • 40Spanish Network on Rare Diseases (CIBERER), Madrid, Spain.
  • 193University Hospital of Cologne, Center for Hereditary Breast and Ovarian Cancer, Cologne, Germany.
  • 195The Ohio State University, Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, Columbus, OH USA.
  • 196University of Kansas Medical Center, Department of Internal Medicine, Division of Oncology, Westwood, KS USA.
  • Vanderbilt University School of Medicine, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Nashville, TN USA.
  • University of Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany.
  • BC Cancer, Population Oncology, Vancouver, BC Canada.
  • 202Institut Curie, Service de Génétique, Paris, France.
  • 205University of Southampton, Faculty of Medicine, Southampton, UK.
  • 207Columbia University, Department of Epidemiology, Mailman School of Public Health, New York, NY USA.
  • 208Odense University Hospital, Department of Clinical Genetics, Odence C, Denmark.
  • Magee-Womens Hospital, University of Pittsburgh School of Medicine, Department of Medicine, Pittsburgh, PA USA.
  • 211Leiden University Medical Center, Department of Surgery, Leiden, The Netherlands.
  • 213Beth Israel Deaconess Medical Center, Department of Medical Oncology, Boston, MA USA.
  • Helios Clinics Berlin-Buch, Department of Gynecology and Obstetrics, Berlin, Germany.
  • 215Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Division of Functional onco-genomics and genetics, Aviano, Italy.
  • 216City of Hope, Clinical Cancer Genetics, Duarte, CA USA.
  • Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
  • 219QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, QLD Australia.
  • 220The Ohio State University, Department of Cancer Biology and Genetics, Columbus, OH USA.
  • 222University of NSW Sydney, School of Women's and Children's Health, Faculty of Medicine, Sydney, NSW Australia.
  • The Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK.
  • 226Columbia University, Departments of Pediatrics and Medicine, New York, NY USA.
  • 227The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Division of Molecular Pathology, Amsterdam, The Netherlands.
Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Related CDAS Studies
Related CDAS Projects