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A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

  • Epidemiology
  • Published:
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Abstract

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10−6 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10−7) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.

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Abbreviations

ARF:

Alternate reading frame of the INK4a/CDKN2A locus

BCAC:

Breast Cancer Association Consortium

CGEMS:

Cancer Genetic Markers of Susceptibility Project

CI:

Confidence interval

DNE:

Delta/notch-like epidermal growth factor-like repeat containing

EPT:

Estrogen-progestagen combined therapy

ET:

Estrogen-only therapy

FBXO36:

F-box protein 36

HWE:

Hardy-Weinberg equilibrium

IBS:

Identical by state

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

MALDI-TOF MS:

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

MARIE:

Mammary Carcinoma Risk Factor Investigation

MHT:

Menopausal hormone therapy

OR:

Odds ratio

QC:

Quality control

SASBAC:

Singapore and Sweden Breast Cancer Study

SET:

Suppressor of variegation, enhancer of zeste, and Trithorax

SETBP1:

SET binding protein

SNP:

Single nucleotide polymorphism

TRIP12:

Thyroid hormone receptor interactor 12

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Acknowledgments

We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. In particular, we thank: Tracy Slanger, Renate Birr, Ursula Eilber, Belinda Kaspereit, N. Knese, Kathi Smit, and Nicole Knese (German Cancer Research Center, Heidelberg, Germany), Elke Mutschelknauss, W. Busch, (German Research Center for Environmental Health, Neuherberg, Germany), M. Schick, R. Fischer and B. Korn (Genomics and Proteomics Core Facilities, German Cancer Research Center, Heidelberg, Germany), W. Höppner and Ramona Salazar (BioGlobe GmbH, Hamburg, Germany), Eik Vettorazzi (Institute for Biostatistics and Epidemiology, University Medical Centre, Hamburg, Germany) (MARIE study); Eileen Williams, Elaine Ryder-Mills and Kara Sargus (British Breast Cancer Study); the GENICA (Gene Environment Interaction and Breast Cancer in Germany) network: Christina Justenhoven (Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, University of Tübingen, Germany), Yon-Dschun Ko and Christian Baisch (Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany), Hans-Peter Fischer (Institute of Pathology, University of Bonn, Bonn, Germany), Ute Hamann (Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany), Thomas Brüning, Beate Pesch, Sylvia Rabstein and Anne Lotz (Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany), Volker Harth (Institute and Outpatient Clinic of Occupational Medicine, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany) (GENICA (Gene Environment Interaction and Breast Cancer in Germany) study); Eija Myöhänen, Helena Kemiläinen (Kuopio Breast Cancer Project); Irene Masunaka (UCI Breast Cancer Study). This work was supported by the Federal Ministry of Education and Research (BMBF) Germany grants 01KH0402, 01KH0408, 01KH0409 and the European Community’s Seventh Framework Programme (Collaborative Oncological Gene Environment Study) [grant agreement number 223175, grant number HEALTH-F2-2009-223175]. The MARIE study was supported by the Deutsche Krebshilfe e.V., grant number 70-2892-BR I, the German Cancer Research Center (DKFZ) and the Hamburg Cancer Society. Genotyping in the BCAC studies was funded by CR-UNITED KINGDOM [C1287/A10118, C1287/A7497]. Meetings of the BCAC have been funded by the European Union COST (European Cooperation in Science and Technology) programme [BM0606]. D.F.E. is a Principal Research Fellow of CR (Cancer Research) –United Kingdom. The BBCS (British Breast Cancer Study) is funded by Cancer Research United Kingdom and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Sécurité Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The GENICA (Gene Environment Interaction and Breast Cancer in Germany) was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0401, 01KH0402, 01KH0410, and 01KH0411, the Robert Bosch Foundation, Stuttgart, German Cancer Research Center (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. The MCBCS (Mayo Clinic Breast Cancer Study) was supported by the NIH (National Institute of Health) grants [CA122340, CA128978], an NIH (National Institute of Health) Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], the Breast Cancer Research Foundation, and the Komen Race for the Cure. The Nurses’ Health Studies are supported by US NIH (National Institute of Health) grants CA65725, CA87969, CA49449, CA67262, CA50385 and 5UO1CA098233. The work on SASBAC (Singapore and Sweden Breast Cancer Study) was supported by National Institutes of Health (RO1 CA58427), the Märit and Hans Rausing’s Initiative against Breast Cancer, and the Agency for Science, Technology and Research (A*STAR). KH was supported by the Swedish Research Council (523-2006-972). KC was financed by the Swedish Cancer Society (5128-B07-01PAF). The TWBCS (Taiwanese Breast Cancer Study) is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS (UCI Breast Cancer Study) component of this research was supported by the NIH (National Institute of Health) [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420].

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Rebecca Hein, Lars Beckmann, Petra Seibold, Sabine Behrens & Jenny Chang-Claude

  2. PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

    Rebecca Hein

  3. Department of Cancer Epidemiology, Clinical Cancer Registry, University Cancer Center and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany

    Dieter Flesch-Janys

  4. Congenics AG, Hamburg, Germany

    Norbert Dahmen

  5. Foundation for Quality and Efficiency in Health Care (IQWIG), Cologne, Germany

    Lars Beckmann

  6. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Sara Lindström & Peter Kraft

  7. Department of Epidemiology, Harvard School Of Public Health, Boston, MA, 02138, USA

    Sara Lindström, Susan E. Hankinson & Peter Kraft

  8. Department of Biostatistics, Harvard School Of Public Health, Boston, MA, 02138, USA

    Sara Lindström & Peter Kraft

  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Nils Schoof, Kamila Czene, Keith Humphreys & Per Hall

  10. Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Munich, Germany

    Kirstin Mittelstraß & Thomas Illig

  11. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany

    Thomas Illig

  12. Human Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore, 138672, Singapore

    Jingmei Li & Jianjun Liu

  13. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Janet E. Olson, Xianshu Wang & Fergus J. Couch

  14. Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France

    Thérèse Truong, Florence Menegaux & Pascal Guénel

  15. University Paris-Sud, UMRS 1018, Villejuif, France

    Thérèse Truong, Florence Menegaux & Pascal Guénel

  16. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Isabel dos Santos Silva & Julian Peto

  17. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Nichola Johnson

  18. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, University of Tübingen, Tübingen, Germany

    Hiltrud Brauch

  19. Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan

    Shou-Tung Chen

  20. Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan

    Jyh-Cherng Yu

  21. Department of Epidemiology, School of Medicine, University of California, Irvine, CA, USA

    Argyrios Ziogas

  22. School of Medicine, Institute of Clinical Medicine, Oncology, Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland

    Vesa Kataja

  23. Cancer Center, Kuopio University Hospital, Kuopio, Finland

    Vesa Kataja

  24. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

    Veli-Matti Kosma & Arto Mannermaa

  25. Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland

    Veli-Matti Kosma & Arto Mannermaa

  26. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland

    Veli-Matti Kosma & Arto Mannermaa

  27. Department of Epidemiology, University of California Irvine, Irvine, CA, USA

    Hoda Anton-Culver

  28. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Chen-Yang Shen

  29. Taiwan Biobank, Taipei, Taiwan

    Chen-Yang Shen

  30. Centre for Cancer Genetic Epidemiology, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Cambridge, UK

    Douglas F. Easton

Authors
  1. Rebecca Hein
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  2. Dieter Flesch-Janys
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  3. Norbert Dahmen
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  4. Lars Beckmann
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  14. Jianjun Liu
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  15. Janet E. Olson
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  16. Xianshu Wang
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  19. Florence Menegaux
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  20. Isabel dos Santos Silva
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  23. Jyh-Cherng Yu
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  30. Hiltrud Brauch
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  31. Julian Peto
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  35. Douglas F. Easton
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  36. Per Hall
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  37. Jenny Chang-Claude
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Consortia

The GENICA Network

Corresponding author

Correspondence to Jenny Chang-Claude.

Additional information

Rebecca Hein and Dieter Flesch-Janys contributed equally to this study.

This study was conducted on behalf of the Breast Cancer Association Consortium.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 49 kb)

Supplementary material 2 (PDF 29 kb)

Supplementary material 3 (PDF 137 kb)

Supplementary material 4 (PDF 76 kb)

Supplementary material 5 (PDF 71 kb)

Supplementary material 6 (PDF 153 kb)

Supplementary material 7 (PDF 155 kb)

10549_2013_2443_MOESM8_ESM.tif

Supplementary Fig. 1: Linkage disequilibrium blocks on chromosome 7, position 71,000,000–71,600,000. Figure legend: Linkage disequilibrium (LD) in terms of D′ between rs2909969 and CALN1 on chromosome 7. LD blocks were generated using data from the HapMap project. The intensity of the colour is proportional to the strength of the LD for the SNP pair. Dark red indicates D‘=1. (TIFF 433 kb)

10549_2013_2443_MOESM9_ESM.tif

Supplementary Fig. 2: Linkage disequilibrium blocks on chromosome 18, position 40,850,000–41,000,000. Figure legend: Linkage disequilibrium (LD) in terms of D′ between rs1942574 and SETBP1 on chromosome 18. LD blocks were generated using data from the HapMap project. The intensity of the colour is proportional to the strength of the LD for the SNP pair. Dark red indicates D′=1. (TIFF 519 kb)

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Hein, R., Flesch-Janys, D., Dahmen, N. et al. A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication. Breast Cancer Res Treat 138, 529–542 (2013). https://doi.org/10.1007/s10549-013-2443-z

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  • DOI: https://doi.org/10.1007/s10549-013-2443-z

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