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Two truncating variants in FANCC and breast cancer risk.

About this Publication
Title
Two truncating variants in FANCC and breast cancer risk.
Pubmed ID
31467304 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Sci Rep. 2019 Aug 29; Volume 9 (Issue 1): Pages 12524
Authors
Dörk T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, Ahearn T, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Augustinsson A, Freeman LEB, Beckmann MW, Beeghly-Fadiel A, Behrens S, Bermisheva M, Blomqvist C, Bogdanova NV, Bojesen SE, ...show more Brauch H, Brenner H, Burwinkel B, Canzian F, Chan TL, Chang-Claude J, Chanock SJ, Choi JY, Christiansen H, Clarke CL, Couch FJ, Czene K, Daly MB, Dos-Santos-Silva I, Dwek M, Eccles DM, Ekici AB, Eriksson M, Evans DG, Fasching PA, Figueroa J, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, Gao C, Gapstur SM, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Goldberg MS, Goldgar DE, Guénel P, Haeberle L, Haiman CA, Håkansson N, Hall P, Hamann U, Hartman M, Hauke J, Hein A, Hillemanns P, Hogervorst FBL, Hooning MJ, Hopper JL, Howell T, Huo D, Ito H, Iwasaki M, Jakubowska A, Janni W, John EM, Jung A, Kaaks R, Kang D, Kapoor PM, Khusnutdinova E, Kim SW, Kitahara CM, Koutros S, Kraft P, Kristensen VN, Kwong A, Lambrechts D, Marchand LL, Li J, Lindström S, Linet M, Lo WY, Long J, Lophatananon A, Lubiński J, Manoochehri M, Manoukian S, Margolin S, Martinez E, Matsuo K, Mavroudis D, Meindl A, Menon U, Milne RL, Mohd Taib NA, Muir K, Mulligan AM, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Offit K, Olopade OI, Olshan AF, Olson JE, Olsson H, Park SK, Park-Simon TW, Peto J, Plaseska-Karanfilska D, Pohl-Rescigno E, Presneau N, Rack B, Radice P, Rashid MU, Rennert G, Rennert HS, Romero A, Ruebner M, Saloustros E, Schmidt MK, Schmutzler RK, Schneider MO, Schoemaker MJ, Scott C, Shen CY, Shu XO, Simard J, Slager S, Smichkoska S, Southey MC, Spinelli JJ, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper WJ, Teo SH, Terry MB, Toland AE, Tollenaar RAEM, Torres D, Torres-Mejía G, Troester MA, Truong T, Tsugane S, Untch M, Vachon CM, Ouweland AMWVD, Veen EMV, Vijai J, Wendt C, Wolk A, Yu JC, Zheng W, Ziogas A, Ziv E, ABCTB Investigators, NBCS Collaborators, Dunning AM, Pharoah PDP, Schindler D, Devilee P, Easton DF
Affiliations
  • Gynaecology Research Unit, Hannover Medical School, Hannover, Germany. doerk.thilo@mh-hannover.de.
  • Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 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, ON, Canada.
  • Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
  • Division of Clinical Epidemiology and Aging Research, C070, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
...show more
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 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 Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong.
  • Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
  • Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
  • Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
  • Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
  • Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
  • Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  • Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • School of Public Health, Curtin University, Perth, Western Australia, Australia.
  • Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
  • Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Department of Medicine, McGill University, Montréal, QC, Canada.
  • Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
  • Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  • Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Division of Cancer Sciences, University of Manchester, Manchester, UK.
  • Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
  • Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
  • Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
  • Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
  • Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea.
  • Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
  • VIB Center for Cancer Biology, VIB, Leuven, Belgium.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
  • Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
  • Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
  • Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
  • Department of Oncology, Södersjukhuset, Stockholm, Sweden.
  • Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
  • Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany.
  • MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
  • Breast Cancer Research Unit, UM Cancer Research Institute, University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
  • Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
  • Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
  • Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • Department of Oncology, University Hospital of Larissa, Larissa, Greece.
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
  • Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of Macedonia.
  • Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
  • Population Oncology, BC Cancer, Vancouver, BC, Canada.
  • Faculty of Medicine, University of Southampton, Southampton, UK.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
  • Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
  • Center for Population Health Research, National Institute of Public Health, Mexico, Mexico.
  • Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
  • Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
  • Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
  • Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
  • Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Institute of Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany.
  • Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Abstract

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

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