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Sci Rep. 2019 Aug 29;9(1):12524. doi: 10.1038/s41598-019-48804-y.

Two truncating variants in FANCC and breast cancer risk.

Dörk T1, Peterlongo P2, Mannermaa A3,4,5, Bolla MK6, Wang Q6, Dennis J6, Ahearn T7, Andrulis IL8,9, Anton-Culver H10, Arndt V11, Aronson KJ12, Augustinsson A13, Freeman LEB7, Beckmann MW14, Beeghly-Fadiel A15, Behrens S16, Bermisheva M17, Blomqvist C18,19, Bogdanova NV20,21,22, Bojesen SE23,24,25, Brauch H26,27,28, Brenner H11,27,29, Burwinkel B30,31, Canzian F32, Chan TL33,34, Chang-Claude J16,35, Chanock SJ7, Choi JY36,37, Christiansen H21, Clarke CL38, Couch FJ39, Czene K40, Daly MB41, Dos-Santos-Silva I42, Dwek M43, Eccles DM44, Ekici AB45, Eriksson M40, Evans DG46,47, Fasching PA14,48, Figueroa J7,49,50, Flyger H51, Fritschi L52, Gabrielson M40, Gago-Dominguez M53,54, Gao C55,56, Gapstur SM57, García-Closas M7,58, García-Sáenz JA59, Gaudet MM57, Giles GG60,61,62, Goldberg MS63,64, Goldgar DE65, Guénel P66, Haeberle L67, Haiman CA68, Håkansson N69, Hall P40,70, Hamann U71, Hartman M72,73, Hauke J74,75,76, Hein A14, Hillemanns P20, Hogervorst FBL77, Hooning MJ78, Hopper JL61, Howell T79, Huo D80, Ito H81,82, Iwasaki M83, Jakubowska A84,85, Janni W86, John EM87, Jung A16, Kaaks R16, Kang D36,37,88, Kapoor PM16,89, Khusnutdinova E17,90, Kim SW91, Kitahara CM92, Koutros S7, Kraft P55,56, Kristensen VN93,94, Kwong A33,95,96, Lambrechts D97,98, Marchand LL99, Li J100, Lindström S101,102, Linet M92, Lo WY26,103, Long J15, Lophatananon A104, Lubiński J84, Manoochehri M71, Manoukian S105, Margolin S70,106, Martinez E54,107, Matsuo K81,82, Mavroudis D108, Meindl A109, Menon U110, Milne RL60,61,111, Mohd Taib NA112, Muir K113,104, Mulligan AM114,115, Neuhausen SL116, Nevanlinna H117, Neven P118, Newman WG46,47, Offit K119,120, Olopade OI80, Olshan AF121, Olson JE122, Olsson H13, Park SK36,37,88, Park-Simon TW20, Peto J42, Plaseska-Karanfilska D123, Pohl-Rescigno E74,75,76, Presneau N43, Rack B86, Radice P124, Rashid MU71,125, Rennert G126, Rennert HS126, Romero A127, Ruebner M67, Saloustros E128, Schmidt MK129,130, Schmutzler RK74,75,76, Schneider MO67, Schoemaker MJ131, Scott C122, Shen CY132,133, Shu XO15, Simard J134, Slager S122, Smichkoska S135, Southey MC111,136, Spinelli JJ137,138, Stone J61,139, Surowy H30,31, Swerdlow AJ131,140, Tamimi RM55,56,141, Tapper WJ142, Teo SH112,143, Terry MB144, Toland AE145, Tollenaar RAEM146, Torres D71,147, Torres-Mejía G148, Troester MA121, Truong T66, Tsugane S149, Untch M150, Vachon CM151, Ouweland AMWVD152, Veen EMV46,47, Vijai J119,120, Wendt C106, Wolk A69,153, Yu JC154, Zheng W15, Ziogas A10, Ziv E155; ABCTB Investigators; NBCS Collaborators, Dunning AM156, Pharoah PDP6,156, Schindler D157, Devilee P158,159, Easton DF6,156.

Author information

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
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
5
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
6
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
7
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
8
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
9
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
10
Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
11
Division of Clinical Epidemiology and Aging Research, C070, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12
Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
13
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
14
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
15
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
16
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
17
Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
18
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
19
Department of Oncology, Örebro University Hospital, Örebro, Sweden.
20
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
21
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
22
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
23
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
24
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
25
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
26
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
27
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
28
iFIT Cluster of Excellence, University of Tübingen, Tübingen, Germany.
29
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
30
Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
31
Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
32
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
33
Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong.
34
Department of Pathology, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.
35
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
36
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
37
Cancer Research Institute, Seoul National University, Seoul, Korea.
38
Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
39
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
40
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
41
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
42
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
43
Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
44
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
45
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
46
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.
47
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
48
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
49
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
50
Cancer Research UK Edinburgh Centre, Edinburgh, UK.
51
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
52
School of Public Health, Curtin University, Perth, Western Australia, Australia.
53
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.
54
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
55
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
56
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
57
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
58
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
59
Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
60
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
61
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
62
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
63
Department of Medicine, McGill University, Montréal, QC, Canada.
64
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
65
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
66
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
67
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
68
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
69
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
70
Department of Oncology, Södersjukhuset, Stockholm, Sweden.
71
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
72
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
73
Department of Surgery, National University Health System, Singapore, Singapore.
74
Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
75
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
76
Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
77
Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
78
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
79
Division of Cancer Sciences, University of Manchester, Manchester, UK.
80
Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
81
Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
82
Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
83
Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
84
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
85
Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
86
Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
87
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
88
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
89
Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
90
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
91
Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea.
92
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
93
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
94
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
95
Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong.
96
Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.
97
VIB Center for Cancer Biology, VIB, Leuven, Belgium.
98
Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
99
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
100
Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
101
Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
102
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
103
University of Tübingen, Tübingen, Germany.
104
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.
105
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
106
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
107
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
108
Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
109
Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany.
110
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
111
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
112
Breast Cancer Research Unit, UM Cancer Research Institute, University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
113
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
114
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
115
Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
116
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
117
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
118
Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
119
Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
120
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
121
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.
122
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
123
Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
124
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
125
Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
126
Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
127
Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
128
Department of Oncology, University Hospital of Larissa, Larissa, Greece.
129
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
130
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
131
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
132
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
133
School of Public Health, China Medical University, Taichung, Taiwan.
134
Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
135
Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of Macedonia.
136
Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
137
Population Oncology, BC Cancer, Vancouver, BC, Canada.
138
School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
139
The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia.
140
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
141
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
142
Faculty of Medicine, University of Southampton, Southampton, UK.
143
Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
144
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
145
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
146
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
147
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
148
Center for Population Health Research, National Institute of Public Health, Mexico, Mexico.
149
Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
150
Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
151
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
152
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
153
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
154
Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
155
Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
156
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
157
Institute of Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany.
158
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
159
Department of Human Genetics, 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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