Comparative Study

. 2013 Nov 4;20(6):875-87.

doi: 10.1530/ERC-13-0349. Print 2013 Dec.

Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study

Anja Rudolph¹, Rebecca Hein, Sara Lindström, Lars Beckmann, Sabine Behrens, Jianjun Liu, Hugues Aschard, Manjeet K Bolla, Jean Wang, Thérèse Truong, Emilie Cordina-Duverger, Florence Menegaux, Thomas Brüning, Volker Harth; GENICA Network; Gianluca Severi, Laura Baglietto, Melissa Southey, Stephen J Chanock, Jolanta Lissowska, Jonine D Figueroa, Mikael Eriksson, Keith Humpreys, Hatef Darabi, Janet E Olson, Kristen N Stevens, Celine M Vachon, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Penny M Webb; kConFab Investigators; AOCS Management Group; Pascal Guénel, Hiltrud Brauch, Graham Giles, Montserrat García-Closas, Kamila Czene, Georgia Chenevix-Trench, Fergus J Couch, Irene L Andrulis, Anthony Swerdlow, David J Hunter, Dieter Flesch-Janys, Douglas F Easton, Per Hall, Heli Nevanlinna, Peter Kraft, Jenny Chang-Claude; Breast Cancer Association Consortium

Collaborators, Affiliations

Collaborators

Douglas F Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Andrew Berchuck, Rosalind A Eeles, Douglas F Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch, Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch, Ken Offit, Joe Dennis, Alison M Dunning, Andrew Lee, Ed Dicks, Craig Luccarini, Javier Benitez, Anna Gonzalez-Neira, Jacques Simard, Daniel C Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière, Frederic Robidoux, Stig E Bojesen, Sune F Nielsen, Borge G Nordestgaard, Julie M Cunningham, Sharon A Windebank, Christopher A Hilker, Jeffrey Meyer, Ursula Eilber, Muhabbet Celik, Teresa Selander, Nayana Weerasooriya, Louise Brinton, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner, Margarete Fischer, Wing-Yee Lo, Yon-Dschun Ko, Christian Baisch, Hans-Peter Fischer, Ute Hamann, Thomas Brüning, Beate Pesch, Sylvia Rabstein, Anne Lotz, Volker Harth, Heather Thorne, Eveline Niedermayr, D Bowtell, G Chenevix- Trench, A deFazio, D Gertig, A Green, P Webb, A Green, P Parsons, N Hayward, P Webb, D Whiteman, A Green, P Parsons, N Hayward, P M Webb, D Whiteman

Affiliation

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Foundation for Quality and Efficiency in Health Care (IQWIG), Cologne, Germany Human Genetics, Genome Institute of Singapore, Singapore, Singapore Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK INSERM (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France Unité Mixte de Recherche Scientifique (UMRS) 1018, University Paris-Sud, Villejuif, France Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany Institute for Occupational Medicine and Maritime Medicine, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia Division of Cancer Epidemiology and Genetics, N

PMID: 24080446
PMCID: PMC3863710
DOI: 10.1530/ERC-13-0349

Comparative Study

Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study

Anja Rudolph et al. Endocr Relat Cancer. 2013.

. 2013 Nov 4;20(6):875-87.

doi: 10.1530/ERC-13-0349. Print 2013 Dec.

Authors

Collaborators

Douglas F Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Andrew Berchuck, Rosalind A Eeles, Douglas F Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch, Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch, Ken Offit, Joe Dennis, Alison M Dunning, Andrew Lee, Ed Dicks, Craig Luccarini, Javier Benitez, Anna Gonzalez-Neira, Jacques Simard, Daniel C Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière, Frederic Robidoux, Stig E Bojesen, Sune F Nielsen, Borge G Nordestgaard, Julie M Cunningham, Sharon A Windebank, Christopher A Hilker, Jeffrey Meyer, Ursula Eilber, Muhabbet Celik, Teresa Selander, Nayana Weerasooriya, Louise Brinton, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner, Margarete Fischer, Wing-Yee Lo, Yon-Dschun Ko, Christian Baisch, Hans-Peter Fischer, Ute Hamann, Thomas Brüning, Beate Pesch, Sylvia Rabstein, Anne Lotz, Volker Harth, Heather Thorne, Eveline Niedermayr, D Bowtell, G Chenevix- Trench, A deFazio, D Gertig, A Green, P Webb, A Green, P Parsons, N Hayward, P Webb, D Whiteman, A Green, P Parsons, N Hayward, P M Webb, D Whiteman

Affiliation

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Foundation for Quality and Efficiency in Health Care (IQWIG), Cologne, Germany Human Genetics, Genome Institute of Singapore, Singapore, Singapore Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK INSERM (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France Unité Mixte de Recherche Scientifique (UMRS) 1018, University Paris-Sud, Villejuif, France Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany Institute for Occupational Medicine and Maritime Medicine, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia Division of Cancer Epidemiology and Genetics, N

PMID: 24080446
PMCID: PMC3863710
DOI: 10.1530/ERC-13-0349

Abstract

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint≤4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint≤4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7 × 10(-5)), one SNP in CD80 (combined Pint≤8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

Keywords: breast cancer; genetic variation; genome-wide; menopausal hormone therapy.

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Conflict of interest statement

DECLARATION OF INTEREST

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

**Figure 1**
Diagram describing numbers of participants, investigated SNPs and conducted analyses at each stage

**Figure 2**
Odd ratios for (A) overall breast cancer and (B) lobular breast cancer risk associated with current use of menopausal hormone therapy in categories defined by polygenic scores

See this image and copyright information in PMC

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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study

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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study

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Abstract

Conflict of interest statement

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References

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