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

Taru A Muranen; Dario Greco; Carl Blomqvist; Kristiina Aittomäki; Sofia Khan; Frans Hogervorst; Senno Verhoef; Paul D P Pharoah; Alison M Dunning; Mitul Shah; Robert Luben; Stig E Bojesen; Børge G Nordestgaard; Minouk Schoemaker; Anthony Swerdlow; Montserrat García-Closas; Jonine Figueroa; Thilo Dörk; Natalia V Bogdanova; Per Hall; Jingmei Li; Elza Khusnutdinova; Marina Bermisheva; Vessela Kristensen; Anne-Lise Borresen-Dale; NBCS Investigators; Julian Peto; Isabel Dos Santos Silva; Fergus J Couch; Janet E Olson; Peter Hillemans; Tjoung-Won Park-Simon; Hiltrud Brauch; Ute Hamann; Barbara Burwinkel; Frederik Marme; Alfons Meindl; Rita K Schmutzler; Angela Cox; Simon S Cross; Elinor J Sawyer; Ian Tomlinson; Diether Lambrechts; Matthieu Moisse; Annika Lindblom; Sara Margolin; Antoinette Hollestelle; John W M Martens; Peter A Fasching; Matthias W Beckmann; Irene L Andrulis; Julia A Knight; kConFab/AOCS Investigators; Hoda Anton-Culver; Argyrios Ziogas; Graham G Giles; Roger L Milne; Hermann Brenner; Volker Arndt; Arto Mannermaa; Veli-Matti Kosma; Jenny Chang-Claude; Anja Rudolph; Peter Devilee; Caroline Seynaeve; John L Hopper; Melissa C Southey; Esther M John; Alice S Whittemore; Manjeet K Bolla; Qin Wang; Kyriaki Michailidou; Joe Dennis; Douglas F Easton; Marjanka K Schmidt; Heli Nevanlinna

doi:10.1038/gim.2016.147

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

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

Authors

Taru A Muranen¹, Dario Greco², Carl Blomqvist³, Kristiina Aittomäki⁴, Sofia Khan¹, Frans Hogervorst⁵, Senno Verhoef⁵, Paul D P Pharoah^{6

7}, Alison M Dunning⁶, Mitul Shah⁶, Robert Luben⁸, Stig E Bojesen^{9

10

11}, Børge G Nordestgaard^{9

10

11}, Minouk Schoemaker¹², Anthony Swerdlow^{12

13}, Montserrat García-Closas^{12

14}, Jonine Figueroa¹⁴, Thilo Dörk¹⁵, Natalia V Bogdanova¹⁶, Per Hall¹⁷, Jingmei Li¹⁷, Elza Khusnutdinova^{18

19}, Marina Bermisheva^{15

19}, Vessela Kristensen^{20

21

22}, Anne-Lise Borresen-Dale^{20

22}; NBCS Investigators^{20

21

22

23

24

25

26

27

28

29

30

31

32

33

34}; Julian Peto³⁵, Isabel Dos Santos Silva³⁵, Fergus J Couch³⁶, Janet E Olson³⁷, Peter Hillemans¹⁵, Tjoung-Won Park-Simon¹⁵, Hiltrud Brauch^{38

39

40}, Ute Hamann⁴¹, Barbara Burwinkel^{42

43}, Frederik Marme^{43

44}, Alfons Meindl⁴⁵, Rita K Schmutzler^{46

47

48}, Angela Cox⁴⁹, Simon S Cross⁵⁰, Elinor J Sawyer⁵¹, Ian Tomlinson⁵², Diether Lambrechts^{53

54}, Matthieu Moisse⁵³, Annika Lindblom⁵⁵, Sara Margolin⁵⁶, Antoinette Hollestelle⁵⁷, John W M Martens⁵⁷, Peter A Fasching^{58

59}, Matthias W Beckmann⁵⁸, Irene L Andrulis^{60

61}, Julia A Knight^{62

63}; kConFab/AOCS Investigators⁶⁴; Hoda Anton-Culver⁶⁵, Argyrios Ziogas⁶⁵, Graham G Giles^{66

67}, Roger L Milne^{66

67}, Hermann Brenner^{38

68

69}, Volker Arndt⁶⁹, Arto Mannermaa^{70

71

72}, Veli-Matti Kosma^{70

71

72}, Jenny Chang-Claude⁷³, Anja Rudolph⁷³, Peter Devilee^{74

75}, Caroline Seynaeve⁵⁷, John L Hopper⁶⁶, Melissa C Southey⁷⁶, Esther M John^{77

78

79}, Alice S Whittemore^{78

79}, Manjeet K Bolla⁷, Qin Wang⁷, Kyriaki Michailidou^{7

80}, Joe Dennis⁷, Douglas F Easton^{6

7}, Marjanka K Schmidt⁵, Heli Nevanlinna¹

Affiliations

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.

MeSH terms

Breast Neoplasms / genetics*
Checkpoint Kinase 2 / genetics*
Female
Genes, Modifier
Genetic Predisposition to Disease
Humans
Odds Ratio
Penetrance
Sequence Deletion*

Substances

Checkpoint Kinase 2
CHEK2 protein, human

Abstract

MeSH terms

Substances

Grants and funding