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.
Highlights
Gynecology and Obstetrics, Comprehensive Cancer Center estrogen receptor (ER)-EMN, University Hospital Erlangen, FriedrichAlexander-University Erlangen-Nuremberg, Erlangen, Germany. 15Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. 16Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 17Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia. 18Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 19Department of Oncology, Örebro University Hospital, Örebro, Sweden. 20Department of Radiation Oncology, Hannover Medical School, Hannover, Germany. 21N.N
In Europeans, the two FANCC variants were observed in 25/64,760 cases (14 with p.R185X, 11 with p.R548X) and in 26/49,793 controls (18 with p.R185X, 8 with p.R548X)
We found no evidence for an association with estrogen receptor (ER)-negative or ER-positive disease, nor for subsets of disease defined by age at diagnosis (
Summary
Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, FriedrichAlexander-University Erlangen-Nuremberg, Erlangen, Germany. 15Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. 16Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 17Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia. 18Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 19Department of Oncology, Örebro University Hospital, Örebro, Sweden. 20Department of Radiation Oncology, Hannover Medical School, Hannover, Germany. 21N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus. 22Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 23Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 24Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 25Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. 26University of Tübingen, Tübingen, Germany. 27German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 28Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. 29Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany. 30Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany. 31Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 32Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong. 33Department of Pathology, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong. 34Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 35Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. 36Cancer Research Institute, Seoul National University, Seoul, Korea. 37Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia. 38Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 39Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 40Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA. 41Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 42Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK. 43Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK. 44Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 45Division 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. 46Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 47David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA. 48Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK. 49Cancer Research UK Edinburgh Centre, Edinburgh, UK. 50Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 51School of Public Health, Curtin University, Perth, Western Australia, Australia. 52Genomic Medicine Group, Galician Foundation of Genomic Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 59Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. 60Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. 61Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. 62Department of Medicine, McGill University, Montréal, QC, Canada. 63Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada. 64Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA. 65Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France. 66Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 67Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 68Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 69Department of Oncology, Södersjukhuset, Stockholm, Sweden. 70Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. 71Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. 72Department of Surgery, National University Health System, Singapore, Singapore. 73Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 74Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 75Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 76Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands. 77Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 78Division of Cancer Sciences, University of Manchester, Manchester, UK. 79Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA. 80Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. 81Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 82Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan. 83Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 84Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. 85Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 86Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. 87Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea. 88Faculty of Medicine, University of Heidelberg, Heidelberg, Germany. 89Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia. 90Department of Surgery, Daerim Saint Mary’s Hospital, Seoul, Korea. 91Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 92Department of Cancer Genetics, Institute for Cancer Research, Oslo University HospitalRadiumhospitalet, Oslo, Norway. 93Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 94Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong. 95Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong. 96VIB Center for Cancer Biology, VIB, Leuven, Belgium. 97Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium. 98Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. 99Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore. 100Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA. 101Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 102Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK. 103Division 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. 104Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. 105Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden. 106Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. 107Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece. 108Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany. 109MRC
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