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Two truncating variants in FANCC and breast cancer risk

Dörk T 1 , Peterlongo P 2 , Mannermaa A 3 , Bolla MK 4 , Wang Q 4 , Dennis J 4 Show all authors , Ahearn T 5 , Andrulis IL 6 , Anton-Culver H 7 , Arndt V 8 , Aronson KJ 9 , Augustinsson A 10 , Freeman LEB 5 , Beckmann MW 11 , Beeghly-Fadiel A 12 , Behrens S 13 , Bermisheva M 14 , Blomqvist C 15 , Bogdanova NV 16 , Bojesen SE 17 , Brauch H 18 , Brenner H 8 , Burwinkel B 19 , Canzian F 20 , Chan TL 21 , Chang-Claude J 13 , Chanock SJ 5 , Choi JY 22 , Christiansen H 23 , Clarke CL 24 , Couch FJ 25 , Czene K 26 , Daly MB 27 , Dos-Santos-Silva I 28 , Dwek M 29 , Eccles DM 30 , Ekici AB 31 , Eriksson M 26 , Evans DG 32 , Fasching PA 11 , Figueroa J 5 , Flyger H 33 , Fritschi L 34 , Gabrielson M 26 , Gago-Dominguez M 35 , Gao C 36 , Gapstur SM 37 , García-Closas M 5 , García-Sáenz JA 38 , Gaudet MM 37 , Giles GG 39 , Goldberg MS 40 , Goldgar DE 41 , Guénel P 42 , Haeberle L 43 , Haiman CA 44 , Håkansson N 45 , Hall P 26 , Hamann U 46 , Hartman M 47 , Hauke J 48 , Hein A 11 , Hillemanns P 16 , Hogervorst FBL 49 , Hooning MJ 50 , Hopper JL 51 , Howell T 52 , Huo D 53 , Ito H 54 , Iwasaki M 55 , Jakubowska A 56 , Janni W 57 , John EM 58 , Jung A 13 , Kaaks R 13 , Kang D 22 , Kapoor PM 13 , Khusnutdinova E 14 , Kim SW 59 , Kitahara CM 60 , Koutros S 5 , Kraft P 36 , Kristensen VN 61 , Kwong A 21 , Lambrechts D 62 , Marchand LL 63 , Li J 64 , Lindström S 65 , Linet M 60 , Lo WY 18 , Long J 12 , Lophatananon A 66 , Lubiński J 56 , Manoochehri M 46 , Manoukian S 67 , Margolin S 68 , Martinez E 69 , Matsuo K 54 , Mavroudis D 70 , Meindl A 71 , Menon U 72 , Milne RL 39 , Mohd Taib NA 73 , Muir K 74 , Mulligan AM 75 , Neuhausen SL 76 , Nevanlinna H 77 , Neven P 78 , Newman WG 32 , Offit K 79 , Olopade OI 53 , Olshan AF 80 , Olson JE 81 , Olsson H 10 , Park SK 22 , Park-Simon TW 16 , Peto J 28 , Plaseska-Karanfilska D 82 , Pohl-Rescigno E 48 , Presneau N 29 , Rack B 57 , Radice P 83 , Rashid MU 46 , Rennert G 84 , Rennert HS 84 , Romero A 85 , Ruebner M 43 , Saloustros E 86 , Schmidt MK 87 , Schmutzler RK 48 , Schneider MO 43 , Schoemaker MJ 88 , Scott C 81 , Shen CY 89 , Shu XO 12 , Simard J 90 , Slager S 81 , Smichkoska S 91 , Southey MC 92 , Spinelli JJ 93 , Stone J 51 , Surowy H 19 , Swerdlow AJ 88 , Tamimi RM 36 , Tapper WJ 94 , Teo SH 73 , Terry MB 95 , Toland AE 96 , Tollenaar RAEM 97 , Torres D 46 , Torres-Mejía G 98 , Troester MA 80 , Truong T 42 , Tsugane S 99 , Untch M 100 , Vachon CM 101 , Ouweland AMWVD 102 , Veen EMV 32 , Vijai J 79 , Wendt C 103 , Wolk A 45 , Yu JC 104 , Zheng W 12 , Ziogas A 7 , Ziv E 105 , ABCTB Investigators , NBCS Collaborators , Dunning AM 106 , Pharoah PDP 4 , Schindler D 107 , Devilee P 108 , Easton DF 4

Affiliations 

  • 1 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany. doerk.thilo@mh-hannover.de
  • 2 Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy
  • 3 Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
  • 4 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 5 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
  • 6 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
  • 7 Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA
  • 8 Division of Clinical Epidemiology and Aging Research, C070, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 9 Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada
  • 10 Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
  • 11 Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 12 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  • 13 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 14 Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
  • 15 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 16 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 17 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 18 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  • 19 Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 20 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 21 Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong
  • 22 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
  • 23 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 24 Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
  • 25 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 26 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 27 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
  • 28 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  • 29 Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK
  • 30 Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
  • 31 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 32 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
  • 33 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 34 School of Public Health, Curtin University, Perth, Western Australia, Australia
  • 35 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
  • 36 Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 37 Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
  • 38 Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
  • 39 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 40 Department of Medicine, McGill University, Montréal, QC, Canada
  • 41 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 42 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  • 43 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 44 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 45 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 46 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 47 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • 48 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • 49 Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  • 50 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 51 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  • 52 Division of Cancer Sciences, University of Manchester, Manchester, UK
  • 53 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA
  • 54 Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 55 Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
  • 56 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 57 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  • 58 Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
  • 59 Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea
  • 60 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  • 61 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
  • 62 VIB Center for Cancer Biology, VIB, Leuven, Belgium
  • 63 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 64 Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore
  • 65 Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
  • 66 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
  • 67 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
  • 68 Department of Oncology, Södersjukhuset, Stockholm, Sweden
  • 69 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
  • 70 Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece
  • 71 Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany
  • 72 MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK
  • 73 Breast Cancer Research Unit, UM Cancer Research Institute, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 74 Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
  • 75 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
  • 76 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
  • 77 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 78 Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
  • 79 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  • 80 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
  • 81 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
  • 82 Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia
  • 83 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 84 Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
  • 85 Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain
  • 86 Department of Oncology, University Hospital of Larissa, Larissa, Greece
  • 87 Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 88 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 89 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 90 Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada
  • 91 Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of Macedonia
  • 92 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
  • 93 Population Oncology, BC Cancer, Vancouver, BC, Canada
  • 94 Faculty of Medicine, University of Southampton, Southampton, UK
  • 95 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
  • 96 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
  • 97 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
  • 98 Center for Population Health Research, National Institute of Public Health, Mexico, Mexico
  • 99 Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
  • 100 Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany
  • 101 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
  • 102 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 103 Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  • 104 Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
  • 105 Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
  • 106 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 107 Institute of Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany
  • 108 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Sci Rep, 2019 08 29;9(1):12524.
PMID: 31467304 DOI: 10.1038/s41598-019-48804-y

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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