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Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women

  • Epidemiology
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An Erratum to this article was published on 19 September 2009

Abstract

Recent findings indicate a greater risk of postmenopausal breast cancer with estrogen–progestagen therapy than estrogen monotherapy, and more so for current than past use. Few studies have examined individual genetic susceptibility to the effects of menopausal hormone therapy. We used two population-based case-control studies with 3,155 postmenopausal breast cancer patients and 5,496 controls to evaluate modification of breast cancer risk associated with duration of hormone use by genes involved in hormone metabolism and detoxification. Twenty-eight polymorphisms in eight genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP3A7) and nine genes of phase II enzymes (COMT, GSTM1, GSTM3, GSTP1, GSTT1, SULT1A1, UGT1A1, UGT1A6, UGT2B7) were genotyped. The risk associated with duration of use of combined estrogen–progestagen therapy was significantly modified by genetic polymorphisms located in CYP1B1, GSTP1, and GSTT1. In homozygote carriers of the CYP1B1_142_G and the CYP1B1_355 _T variant alleles, adjusted odds ratios (OR) per year of use were 1.06 (95% confidence interval (CI) = 1.02–1.09) and 1.06 (95% CI = 1.03–1.09), respectively, compared with 1.02 (95% CI = 1.01–1.03) in non-carriers of either polymorphism (p interaction = 0.01). Carriers of the functional GSTT1 allele and the GSTP1_341_T allele were at significantly higher risks associated with hormone use compared with non-carriers (p interaction = 0.0001 and 0.02). CYP1A1_2452_C>A significantly reduced the risk associated with duration of use of estrogen monotherapy (p interaction = 0.01). The finding regarding GSTT1 was still statistically significant after corrections for multiple comparisons. Postmenopausal breast cancer risk associated with hormone therapy may be modified by genetically determined variations in phase I and II enzymes involved in steroid hormone metabolism.

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Acknowledgments

We are indebted to all women who participated in the MARIE and the GENICA breast cancer case-control studies. We gratefully acknowledge support by interviewers, the recruiting hospitals and physicians of the study regions as well as their collaborating pathologists. We thank R. Salazar and W. Höppner from BioGlobe GmBH, Hamburg for the extensive and excellent genotyping work, and S. Behrens, R. Birr, W. Busch, U. Eilber, B. Kaspereit, N. Knese, K. Smit, S. Brod, A. Seidel-Renkert and M. Gilbert for their excellent technical assistance.

The MARIE study was supported by the Deutsche Krebshilfe e.V., grant number 70-2892-BR I and the Hamburg Cancer Society. The GENICA study was supported by the Federal Ministry of Education and Research (BMBF) Germany grants and 01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114 the Robert Bosch Foundation, Stuttgart, Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, and Research Institute of Occupational Medicine of the German Social Accident Insurance (BGFA), Bochum, Germany. The work of the consortium was funded by BMBF Germany grants 01KH0401, 01KH0402, 01KH0410, 01KH0411.

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    The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk

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    The members of the consortium are given in the Appendix.

    An erratum to this article can be found at http://dx.doi.org/10.1007/s10549-009-0529-4

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    Appendix

    Appendix

    Consortium Members include:

    German Cancer Research Center (DKFZ), Heidelberg, Germany: Jenny Chang-Claude, Lars Beckmann, Charlotte Corson, Rebecca Hein, Silke Kropp, Margie Parthimos (Division of Cancer Epidemiology); Thomas Dünnebier, Ute Hamann (Research Group on Molecular Genetics of Breast Cancer); Benedikt Brors, Roland Eils, Marc Zapatka (Division of Theoretical Bioinformatics).

    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP), Stuttgart, and University of Tübingen, Germany: Hiltrud Brauch, Christina Justenhoven.

    University Medical Center Hamburg-Eppendorf, Hamburg, Germany: Dieter Flesch-Janys (Department of Medical Biometry and Epidemiology, Center for Experimental Medicine); Wilhelm Braendle (Department of Gynecological Endocrinology and Reproductive Medicine, Center for Gynaecology, Obstetrics and Pediatrics).

    BGFA—Research Institute of Occupational Medicine of the German Social Accident Insurance, Ruhr University Bochum (Bochum, Germany): Thomas Brüning, Beate Pesch, Anne Spickenheuer

    Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany: Yon-Dschun Ko, Christian Baisch (Department of Internal Medicine).

    Congenics AG, Hamburg, Germany: Norbert Dahmen

    The Writing Group included (in alphabetical order):

    Hiltrud Brauch, Jenny Chang-Claude, Charlotte Corson, Thomas Dünnebier, Ute

    Hamann, Rebecca Hein, Christina Justenhoven, Margie Parthimos, Marc Zapatka

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    The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women. Breast Cancer Res Treat 119, 463–474 (2010). https://doi.org/10.1007/s10549-009-0407-0

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