title: Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.
abstract: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).
  
  
  
  Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.
  
  
  
  The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.
  
  
  
  Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Taru A
authors.identifier: 0000-0002-5895-1808
authors.initials: TA
authors.lastname: Muranen
authors.affiliation: Unit of Systems Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.affiliation: Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Carl
authors.identifier: 0000-0003-3041-1938
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Sofia
authors.identifier: 0000-0003-4185-8882
authors.initials: S
authors.lastname: Khan
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors.forename: Frans
authors.identifier: 0000-0002-5883-9517
authors.initials: F
authors.lastname: Hogervorst
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors.forename: Senno
authors.initials: S
authors.lastname: Verhoef
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.identifier: 0000-0001-8494-732X
authors.initials: PDP
authors.lastname: Pharoah
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Alison M
authors.identifier: 0000-0001-6651-7166
authors.initials: AM
authors.lastname: Dunning
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.affiliation: Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.affiliation: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.|Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.affiliation: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.|Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Minouk
authors.initials: M
authors.lastname: Schoemaker
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.|Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Anthony
authors.identifier: 0000-0001-5550-4159
authors.initials: A
authors.lastname: Swerdlow
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.|Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.affiliation: Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogdanova
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jingmei
authors.identifier: 0000-0001-8587-7511
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.|Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
authors.forename: Elza
authors.initials: E
authors.lastname: Khusnutdinova
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.|Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Bermisheva
authors.affiliation: Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.|Department of Clinical Molecular Biology, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.affiliation: Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borresen-Dale
authors.affiliation: Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.|Department of Clinical Molecular Biology, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Oncology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.|Department of Radiology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.|National Resource Centre for Long-term Studies after Cancer, Cancer Clinic, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.|Department of Breast and Endocrine Surgery, Institute for Clinical Medicine, Ullevaal University Hospital, Oslo, Norway.|Department of Clinical Molecular Biology, Institute of Clinical Medicine, Akershus University Hospital, Lørenskog, Norway.|Department of Oncology, Ullevaal University Hospital, University of Oslo, Oslo, Norway.|Department of Pathology, Akershus University Hospital, Lørenskog, Norway.|Department of Surgery, Akershus University Hospital, Lørenskog, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.|Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.|Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromsø, Norway.|Department of Community Medicine, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Julian
authors.identifier: 0000-0002-1685-8912
authors.initials: J
authors.lastname: Peto
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Dos Santos Silva
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Janet E
authors.identifier: 0000-0003-4944-7789
authors.initials: JE
authors.lastname: Olson
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
authors.forename: Peter
authors.identifier: 0000-0001-9829-3531
authors.initials: P
authors.lastname: Hillemans
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
authors.forename: Tjoung-Won
authors.identifier: 0000-0002-2863-3040
authors.initials: TW
authors.lastname: Park-Simon
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ute
authors.identifier: 0000-0001-6705-7624
authors.initials: U
authors.lastname: Hamann
authors.affiliation: Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Marme
authors.affiliation: Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.|Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.affiliation: Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
authors.forename: Angela
authors.identifier: 0000-0002-5138-1099
authors.initials: A
authors.lastname: Cox
authors.affiliation: Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.affiliation: Research Oncology, Guy's Hospital, King's College London, London, UK.
authors.forename: Elinor J
authors.initials: EJ
authors.lastname: Sawyer
authors.affiliation: Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.|Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Matthieu
authors.identifier: 0000-0001-8880-9311
authors.initials: M
authors.lastname: Moisse
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.identifier: 0000-0001-7675-7569
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Margolin
authors.affiliation: Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Antoinette
authors.identifier: 0000-0003-1166-1966
authors.initials: A
authors.lastname: Hollestelle
authors.affiliation: Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: John W M
authors.initials: JWM
authors.lastname: Martens
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.|David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.affiliation: Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, California, USA.
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, California, USA.
authors.forename: Argyrios
authors.identifier: 0000-0003-4529-3727
authors.initials: A
authors.lastname: Ziogas
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arndt
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center, Kuopio University Hospital, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center, Kuopio University Hospital, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anja
authors.identifier: 0000-0001-7520-2035
authors.initials: A
authors.lastname: Rudolph
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.identifier: 0000-0002-8023-2009
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
authors.forename: John L
authors.identifier: 0000-0002-8567-173X
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
authors.forename: Melissa C
authors.identifier: 0000-0002-6313-9005
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA.|Department of Health Research and Policy - Epidemiology.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.affiliation: Department of Health Research and Policy - Epidemiology.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Bolla
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Qin
authors.identifier: 0000-0002-9139-0627
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Kyriaki
authors.identifier: 0000-0001-7065-1237
authors.initials: K
authors.lastname: Michailidou
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Joe
authors.identifier: 0000-0003-4591-1214
authors.initials: J
authors.lastname: Dennis
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.identifier: 0000-0003-2444-3247
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D005260:Female; D060045:Genes, Modifier; D020022:Genetic Predisposition to Disease; D006801:Humans; D016017:Odds Ratio; D019683:Penetrance; D017384:Sequence Deletion
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human