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J Med Genet. 2016 Dec;53(12):800-811. doi: 10.1136/jmedgenet-2016-103839. Epub 2016 Sep 5.

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Southey MC1, Goldgar DE2, Winqvist R3, Pylkäs K3, Couch F4, Tischkowitz M5, Foulkes WD6, Dennis J7, Michailidou K7, van Rensburg EJ8, Heikkinen T9, Nevanlinna H9, Hopper JL10, Dörk T11, Claes KB12, Reis-Filho J13, Teo ZL1, Radice P14, Catucci I15, Peterlongo P15, Tsimiklis H1, Odefrey FA1, Dowty JG10, Schmidt MK16, Broeks A16, Hogervorst FB16, Verhoef S16, Carpenter J17, Clarke C18, Scott RJ19, Fasching PA20,21, Haeberle L20,22, Ekici AB23, Beckmann MW20, Peto J24, Dos-Santos-Silva I24, Fletcher O25, Johnson N25, Bolla MK7, Sawyer EJ26, Tomlinson I27, Kerin MJ28, Miller N28, Marme F29,30, Burwinkel B29,31, Yang R29,31, Guénel P32,33, Truong T32,33, Menegaux F32,33, Sanchez M32,33, Bojesen S34,35, Nielsen SF34,35, Flyger H36, Benitez J37,38, Zamora MP39, Perez JI40, Menéndez P41, Anton-Culver H42, Neuhausen S43, Ziogas A42, Clarke CA44, Brenner H45,46,47, Arndt V45, Stegmaier C48, Brauch H47,49,50, Brüning T51, Ko YD52, Muranen TA9, Aittomäki K53, Blomqvist C54, Bogdanova NV11,55, Antonenkova NN56, Lindblom A57, Margolin S58, Mannermaa A59,60, Kataja V61,62, Kosma VM59,60, Hartikainen JM59,60, Spurdle AB63, Investigators K64; Australian Ovarian Cancer Study Group, Wauters E65,66, Smeets D65,66, Beuselinck B67, Floris G67, Chang-Claude J68, Rudolph A68, Seibold P68, Flesch-Janys D69, Olson JE70, Vachon C70, Pankratz VS70, McLean C71, Haiman CA72, Henderson BE72, Schumacher F72, Le Marchand L73, Kristensen V74,75, Alnæs GG74, Zheng W76, Hunter DJ77,78, Lindstrom S77,78, Hankinson SE78,79, Kraft P77,78, Andrulis I80,81, Knight JA82,83, Glendon G80, Mulligan AM84,85, Jukkola-Vuorinen A86, Grip M87, Kauppila S88, Devilee P89, Tollenaar RA89, Seynaeve C90,91, Hollestelle A90,91, Garcia-Closas M92, Figueroa J93, Chanock SJ93, Lissowska J94, Czene K95, Darabi H95, Eriksson M95, Eccles DM96, Rafiq S96, Tapper WJ96, Gerty SM96, Hooning MJ91, Martens JW91, Collée JM97, Tilanus-Linthorst M98, Hall P95, Li J99, Brand JS95, Humphreys K95, Cox A100, Reed MW100, Luccarini C101, Baynes C101, Dunning AM101, Hamann U102, Torres D102,103, Ulmer HU104, Rüdiger T105, Jakubowska A106, Lubinski J106, Jaworska K106,107, Durda K106, Slager S70, Toland AE108, Ambrosone CB109, Yannoukakos D110, Swerdlow A111,112, Ashworth A92, Orr N92, Jones M111, González-Neira A37, Pita G37, Alonso MR37, Álvarez N37, Herrero D37, Tessier DC113, Vincent D114, Bacot F114, Simard J115, Dumont M115, Soucy P115, Eeles R116,117, Muir K118, Wiklund F119, Gronberg H119, Schleutker J120,121, Nordestgaard BG122, Weischer M123, Travis RC124, Neal D125, Donovan JL126, Hamdy FC127, Khaw KT128, Stanford JL129,130, Blot WJ131, Thibodeau S4, Schaid DJ70, Kelley JL132, Maier C133,134, Kibel AS135,136, Cybulski C137, Cannon-Albright L138, Butterbach K45, Park J139, Kaneva R140, Batra J141, Teixeira MR142, Kote-Jarai Z116, Olama AA7, Benlloch S7, Renner SP143, Hartmann A144, Hein A143, Ruebner M143, Lambrechts D145,146, Van Nieuwenhuysen E147, Vergote I147, Lambretchs S147, Doherty JA148, Rossing MA149,150, Nickels S151, Eilber U151, Wang-Gohrke S152, Odunsi K153, Sucheston-Campbell LE153, Friel G153, Lurie G154, Killeen JL155, Wilkens LR154, Goodman MT156,157, Runnebaum I158, Hillemanns PA159, Pelttari LM9, Butzow R160, Modugno F161,162, Edwards RP132, Ness RB163, Moysich KB164, du Bois A165,166, Heitz F165,166, Harter P165,166, Kommoss S166,167, Karlan BY168, Walsh C168, Lester J168, Jensen A169, Kjaer SK169,170, Høgdall E169,171, Peissel B172, Bonanni B173, Bernard L174, Goode EL70, Fridley BL175, Vierkant RA70, Cunningham JM4, Larson MC70, Fogarty ZC70, Kalli KR176, Liang D177, Lu KH178, Hildebrandt MA179, Wu X179, Levine DA180, Dao F180, Bisogna M180, Berchuck A181, Iversen ES182, Marks JR183, Akushevich L184, Cramer DW185, Schildkraut J184, Terry KL185, Poole EM186,187, Stampfer M78,186, Tworoger SS186,187, Bandera EV188, Orlow I189, Olson SH189, Bjorge L190,191, Salvesen HB190,191, van Altena AM192, Aben KK193,194,195, Kiemeney LA193, Massuger LF192, Pejovic T196, Bean Y196, Brooks-Wilson A197,198, Kelemen LE199,200, Cook LS201, Le ND202, Górski B137, Gronwald J137, Menkiszak J203, Høgdall CK170, Lundvall L204, Nedergaard L205, Engelholm SA206, Dicks E207, Tyrer J207, Campbell I208, McNeish I209, Paul J210, Siddiqui N211, Glasspool R211, Whittemore AS212, Rothstein JH212, McGuire V212, Sieh W212, Cai H76, Shu XO76, Teten RT213, Sutphen R213, McLaughlin JR214, Narod SA215, Phelan CM216, Monteiro AN216, Fenstermacher D217, Lin HY217, Permuth JB216, Sellers TA216, Chen YA217, Tsai YY216, Chen Z217, Gentry-Maharaj A218, Gayther SA219, Ramus SJ219, Menon U218, Wu AH219, Pearce CL219, Van Den Berg D219, Pike MC219,220, Dansonka-Mieszkowska A221, Plisiecka-Halasa J221, Moes-Sosnowska J221, Kupryjanczyk J221, Pharoah PD207, Song H207, Winship I222,223, Chenevix-Trench G63, Giles GG10,224, Tavtigian SV2, Easton DF7, Milne RL10,224.

Author information

1
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
2
Huntsman Cancer Institute, Salt Lake City, UT, USA.
3
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Nordlab Oulu, Oulu, Finland.
4
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
5
Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, and the Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrooke's Hospital.
6
Program in Cancer Genetics, Department of Human Genetics and Oncology, Lady Davis Institute, and Research Institute, McGill University Health Centre, McGill University, Montreal, Canada.
7
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, UK.
8
Department of Genetics, University of Pretoria, South Africa.
9
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
10
Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
11
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
12
Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
13
Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
14
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
15
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
16
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
17
Australian Breast Cancer Tissue Bank, University of Sydney at the Westmead Institute for Medical Research, NSW, Australia.
18
Centre for Cancer Research, University of Sydney at the Westmead Institute for Medical Research, NSW, Australia.
19
Division of Molecular Medicine, Pathology North, Newcastle and University of Newcastle, NSW, Australia.
20
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
21
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA.
22
Unit of Biostatistics, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
23
Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
24
Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
25
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
26
Division of Cancer Studies, NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, London, UK.
27
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, UK and Oxford NIHR Biomedical Research Centre, Headington, OX3 7LE.
28
Surgery, Lambe Institute for Translational Science, NUIGalway, University Hospital Galway, Galway, Ireland.
29
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
30
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
31
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
32
Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France.
33
University Paris-Sud, UMRS 1018, Villejuif, France.
34
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
35
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
36
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
37
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
38
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
39
Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
40
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
41
Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
42
Department of Epidemiology, University of California Irvine, Irvine, California, USA.
43
Beckman Research Institute of City of Hope, Duarte, California, USA.
44
Cancer Prevention Institute of California, Fremont, California, USA.
45
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
46
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
47
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
48
Saarland Cancer Registry, Saarbrücken, Germany.
49
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart.
50
University of Tübingen, Tübingen, Germany.
51
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University, Bochum (IPA), Germany.
52
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
53
Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
54
Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
55
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
56
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
57
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
58
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
59
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
60
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
61
School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.
62
Biocenter Kuopio, Cancer Center of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
63
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
64
Research Department, Peter MacCallum Cancer Centre and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
65
Vesalius Research Center (VRC), VIB, Leuven, Belgium.
66
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
67
University Hospital Gasthuisberg, Leuven, Belgium.
68
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
69
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
70
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
71
Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
72
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
73
Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA.
74
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
75
Faculty of Medicine (Faculty Division Ahus), University of Oslo (UiO), Norway.
76
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
77
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA.
78
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
79
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
80
Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
81
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
82
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
83
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
84
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
85
Laboratory Medicine Program, University Health Network, Toronto, Ontario; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
86
Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.
87
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
88
Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
89
Department of Surgical Oncology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
90
Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
91
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
92
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
93
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
94
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland.
95
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
96
Faculty of Medicine, University of Southampton (UoS), Southampton UK.
97
Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
98
Department of Surgical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
99
Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
100
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
101
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
102
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
103
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
104
Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany.
105
Institute of Pathology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
106
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
107
Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.
108
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
109
Roswell Park Cancer Institute, Buffalo, New York, USA.
110
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Aghia Paraskevi Attikis, Athens, Greece.
111
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
112
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
113
Centre d'innovation Genome Quebec et University McGill Montreal Quebec, Canada.
114
McGill University, Montreal, Quebec, Canada.
115
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Quebec Research Center. Laval University, Quebec, Canada.
116
The Institute of Cancer Research, London, SM2 5NG, UK.
117
Royal Marsden NHS Foundation Trust, Fulham, London, SW3 6JJ, UK.
118
University of Warwick, Coventry, UK.
119
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
120
Department of Medical Biochemistry and Genetics, University of Turku, and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
121
Institute of Biomedical Technology/BioMediTech, University of Tampere, Tampere, Finland.
122
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
123
Department of Human Genetics University of Utah, Salt Lake City, UT, USA and Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
124
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
125
Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge, UK and Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
126
Professor of Social Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS.
127
Nuffield Department of Surgical Sciences, Old Road Campus Research Building (off Roosevelt Drive), University of Oxford, Headington, Oxford, OX3 7DQ.
128
Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0SR.
129
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
130
Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
131
International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, MD 20850.
132
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
133
Department of Urology, University Hospital Ulm, Germany.
134
Institute of Human Genetics University Hospital Ulm, Germany.
135
Brigham and Women's Hospital/Dana-Farber Cancer Institute, 45 Francis Street- ASB II-3, Boston, MA 02115.
136
Washington University, St Louis, Missouri.
137
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
138
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine.
139
Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, Florida, USA.
140
Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University - Sofia, 2 Zdrave St, 1431, Sofia, Bulgaria.
141
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and Schools of Life Science and Public Health, Queensland University of Technology, Brisbane, Australia.
142
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
143
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany.
144
University Hospital Erlangen, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, German.
145
Vesalius Research Center, VIB, Leuven, Belgium.
146
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium.
147
Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
148
Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Hannover, NH, USA.
149
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
150
Department of Epidemiology, University of Washington, Seattle, WA, USA.
151
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
152
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
153
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY.
154
Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
155
Department of Pathology, Kapiolani Medical Center for Women and Children, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96826, USA.
156
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
157
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
158
Department of Gynecology and Obstetrics, Friedrich Schiller University, Jena University Hospital, Jena, Germany.
159
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
160
Department of Pathology, Helsinki University Central Hospital, Helsinki, 00029 HUS, Finland.
161
University of Pittsburgh Department of Obstetrics, Gynecology and Reproductive Sciences and Ovarian Cancer Center of Excellence Pittsburgh PA USA.
162
University of Pittsburgh Department of Epidemiology, University of Pittsburgh Graduate School of Public Health and Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute Pittsburgh PA USA.
163
The University of Texas School of Public Health, Houston, TX, USA.
164
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.
165
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany.
166
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
167
Tuebingen University Hospital, Department of Women's Health, Tuebingen, Germany.
168
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
169
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
170
Department of Obstetrics and Gynecology, Rigshospitalet, Copenhagen, Denmark.
171
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
172
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
173
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy.
174
Department of Experimental Oncology, Istituto Europeo di Oncologia (IEO), Milan, Italy and Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
175
University of Kansas Medical Center, Kansas City, KS, USA.
176
Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
177
College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA.
178
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
179
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
180
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
181
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.
182
Department of Statistical Science, Duke University, Durham, North Carolina, USA.
183
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
184
Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, North Carolina, USA.
185
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
186
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School.
187
Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.
188
Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, The State University of New Jersey, New Brunswick, NJ, USA.
189
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
190
Department of Gynecology and Obstetrics, Haukeland University Horpital, Bergen, Norway.
191
Centre for Cancer Biomarkers, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
192
Radboud university medical center, Department of Gynaecology, Nijmegen, Netherlands.
193
Radboud university medical centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands.
194
Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands.
195
Department of Obstetrcs & Gynecology, Oregon Health & Science University.
196
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
197
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
198
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC Canada.
199
Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, SC, USA.
200
Hollings Cancer Center, Medical University of South Carolina, SC, USA.
201
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
202
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
203
Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
204
Gyn Clinic, Rigshospitalet, University of Copenhagen, Denmark.
205
Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark.
206
Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark.
207
Department of Oncology, University of Cambridge, Strangeways Research laboratory, Cambridge, UK.
208
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne.
209
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK.
210
The Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN.
211
Department of Gynaecological Oncology, Glasgow Royal Infirmary.
212
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford CA, USA.
213
Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida, USA.
214
Public Health Ontario, Toronto, Canada.
215
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
216
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
217
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
218
Women's Cancer, Institute for Women's Health, UCL, London, United Kingdom.
219
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
220
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
221
Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
222
Department of Medicine, The University of Melbourne Health, Australia.
223
The Royal Melbourne Hospital, Victoria 3050, Australia.
224
Cancer Epidemiology Centre, Cancer Council Victoria, Victoria, Australia.

Abstract

BACKGROUND:

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.

METHODS:

We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.

RESULTS:

For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.

CONCLUSIONS:

This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

KEYWORDS:

Cancer: breast; Cancer: ovary; Cancer: prostate; Genetics; cancer predisposition

PMID:
27595995
PMCID:
PMC5200636
DOI:
10.1136/jmedgenet-2016-103839
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflicts of Interest: None declared.

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