Article
Genetic modifiers of CHEK2*1100delC-associated breast cancer risk
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- (1) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (2) Finnish Institute of Occupational Health, grid.6975.d
- (3) Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (4) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (5) Antoni van Leeuwenhoek Hospital, grid.430814.a
- (6) University of Cambridge, grid.5335.0
- (7) Herlev Hospital, grid.411900.d, Capital Region
- (8) University of Copenhagen, grid.5254.6, KU
- (9) Institute of Cancer Research, grid.18886.3f
- (10) National Cancer Institute, grid.48336.3a
- (11) Hannover Medical School, grid.10423.34
- (12) Karolinska Institute, grid.4714.6
- (13) Bashkir State University, grid.77269.3d
- (14) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
- (15) Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
- (16) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- (17) Oslo University Hospital, grid.55325.34
- (18) Akershus University Hospital, grid.411279.8
- (19) Department of Oncology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
- (20) Department of Oncology, Ullevaal University Hospital, University of Oslo, Oslo, Norway
- (21) Department of Radiology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
- (22) Haukeland University Hospital, grid.412008.f
- (23) National Resource Centre for Long-term Studies after Cancer, Cancer Clinic, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
- (24) The Arctic University of Norway, grid.10919.30
- (25) University Hospital of North Norway, grid.412244.5
- (26) University of Bergen, grid.7914.b
- (27) London School of Hygiene & Tropical Medicine, grid.8991.9
- (28) Mayo Clinic, grid.66875.3a
- (29) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
- (30) University of Tübingen, grid.10392.39
- (31) German Cancer Research Center, grid.7497.d
- (32) Heidelberg University, grid.7700.0
- (33) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
- (34) Technical University of Munich, grid.6936.a
- (35) University Hospital Cologne, grid.411097.a
- (36) University of Cologne, grid.6190.e
- (37) University of Sheffield, grid.11835.3e
- (38) King's College London, grid.13097.3c
- (39) University of Oxford, grid.4991.5
- (40) Flanders Institute for Biotechnology, grid.11486.3a
- (41) KU Leuven, grid.5596.f
- (42) Erasmus University Medical Center, grid.5645.2
- (43) University of California, Los Angeles, grid.19006.3e
- (44) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- (45) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
- (46) University of Toronto, grid.17063.33
- (47) Mount Sinai Hospital, grid.416166.2
- (48) Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia
- (49) University of California, Irvine, grid.266093.8
- (50) Cancer Council Victoria, grid.3263.4
- (51) University of Melbourne, grid.1008.9
- (52) Kuopio University Hospital, grid.410705.7
- (53) University of Eastern Finland, grid.9668.1
- (54) Leiden University Medical Center, grid.10419.3d
- (55) Cancer Prevention Institute of California, grid.280669.3
- (56) Department of Health Research and Policy - Epidemiology,
- (57) Stanford University, grid.168010.e
- (58) Cyprus Institute of Neurology and Genetics, grid.417705.0
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PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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