TY - JOUR
T1 - 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
T2 - A two-stage design with replication
AU - Hein, Rebecca
AU - Flesch-Janys, Dieter
AU - Dahmen, Norbert
AU - Beckmann, Lars
AU - Lindström, Sara
AU - Schoof, Nils
AU - Czene, Kamila
AU - Mittelstraß, Kirstin
AU - Illig, Thomas
AU - Seibold, Petra
AU - Behrens, Sabine
AU - Humphreys, Keith
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Olson, Janet E.
AU - Wang, Xianshu
AU - Hankinson, Susan E.
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Dos Santos Silva, Isabel
AU - Johnson, Nichola
AU - Chen, Shou Tung
AU - Yu, Jyh Cherng
AU - Ziogas, Argyrios
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Mannermaa, Arto
AU - Anton-Culver, Hoda
AU - Shen, Chen Yang
AU - Brauch, Hiltrud
AU - Peto, Julian
AU - Guénel, Pascal
AU - Kraft, Peter
AU - Couch, Fergus J.
AU - Easton, Douglas F.
AU - Hall, Per
AU - Chang-Claude, Jenny
N1 - Funding Information:
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 Ke-miläinen (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 (AN-SES), 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].
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Case-only study
KW - Gene-environment interaction
KW - Genome-wide association study
KW - Menopausal hormone therapy
KW - Polymorphisms
KW - Postmenopausal breast cancer risk
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U2 - 10.1007/s10549-013-2443-z
DO - 10.1007/s10549-013-2443-z
M3 - Article
C2 - 23423446
AN - SCOPUS:84879415699
SN - 0167-6806
VL - 138
SP - 529
EP - 542
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -