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Genet Med. 2017 May;19(5):599-603. doi: 10.1038/gim.2016.147. Epub 2016 Oct 6.

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

Author information

1
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
2
Unit of Systems Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
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
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
6
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
7
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
8
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
9
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
11
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
12
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
13
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
14
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
15
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
16
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
17
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
18
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
19
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
20
Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.
21
Department of Clinical Molecular Biology, Oslo University Hospital, Oslo, Norway.
22
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
23
Department of Oncology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.
24
Department of Radiology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.
25
National Resource Centre for Long-term Studies after Cancer, Cancer Clinic, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.
26
Department of Breast and Endocrine Surgery, Institute for Clinical Medicine, Ullevaal University Hospital, Oslo, Norway.
27
Department of Clinical Molecular Biology, Institute of Clinical Medicine, Akershus University Hospital, Lørenskog, Norway.
28
Department of Oncology, Ullevaal University Hospital, University of Oslo, Oslo, Norway.
29
Department of Pathology, Akershus University Hospital, Lørenskog, Norway.
30
Department of Surgery, Akershus University Hospital, Lørenskog, Norway.
31
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
32
Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.
33
Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromsø, Norway.
34
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.
35
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
36
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
37
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
38
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
39
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
40
University of Tübingen, Tübingen, Germany.
41
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
42
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
43
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
44
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
45
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
46
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
47
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
48
Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
49
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
50
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
51
Research Oncology, Guy's Hospital, King's College London, London, UK.
52
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
53
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
54
Vesalius Research Center, VIB, Leuven, Belgium.
55
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
56
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
57
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
58
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
59
David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA.
60
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
61
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
62
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
63
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
64
Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
65
Department of Epidemiology, University of California Irvine, Irvine, California, USA.
66
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
67
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
68
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
69
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
70
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
71
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
72
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
73
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
74
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
75
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
76
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
77
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA.
78
Department of Health Research and Policy - Epidemiology.
79
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
80
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Abstract

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.

PMID:
27711073
PMCID:
PMC5382131
DOI:
10.1038/gim.2016.147
[Indexed for MEDLINE]
Free PMC Article

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