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Breast cancer: a candidate gene approach across the estrogen metabolic pathway

  • Epidemiology
  • Published:
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Abstract

Polymorphisms within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated 11 genes encoding key proteins of this pathway for their potential contribution to breast cancer risk. Of these CYP17A1, CYP19A1, EPHX1, HSD17B1, SRD5A2, and PPARG2 participate in biosynthesis, CYP1A1, CYP1B1, COMT, GSTP1, and SOD2 in catabolism and detoxification. We performed a population-based case-control study with 688 incident breast cancer cases and 724 controls from Germany and genotyped 18 polymorphisms by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), PCR based RFLP (restriction fragment length polymorphism), and TaqMan® allelic discrimination. Genotype frequencies were compared between cases and controls and odds ratios were calculated by conditional logistic regression. Further statistical analyses were based on cluster analysis, multifactor dimensionality reduction, logic regression, and global testing. Single factor analyses pointed to CYP1B1_1294_GG as a possible breast cancer risk modulator (OR = 2.57; 95% CI: 1.34–4.93) and two way stratification suggested associations between BMI ≥ 30 kg/m2 and COMT_472_GG (P = 0.0076 and P = 0.0026), BMI < 20 kg/m2 and HSD17B1_937_GG (P = 0.0082) as well as CYP17A1_-34_CC and HRT use ≥10 years (P = 0.0063). Following correction for multiple testing none of these associations remained significant. No significant association between breast cancer risk and genetic polymorphisms was observed in multifactor analyses. The tested polymorphisms of the estrogen metabolic pathway may not play a direct role in breast cancer risk. Therefore, future association studies should be extended to other polymorphisms and other regulatory pathways.

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Acknowledgements

We are indebted to all women participating in the GENICA study. We gratefully acknowledge support by interviewers as well as physicians and pathologists of the study region. High-throughput genotyping analyses were supported by Sandra Brod. This work was supported by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation of Medical Research, Stuttgart, Deutsches Krebsforschungszentrum, Heidelberg, Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin Bochum, and Medizinische Universitäts- und Poliklinik, Bonn, Germany.

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Authors and Affiliations

  1. Molecular Mechanisms of Origin and Treatment of Breast Cancer, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany

    Christina Justenhoven & Hiltrud Brauch

  2. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

    Ute Hamann & Michael Gilbert

  3. Department of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

    Falk Schubert, Marc Zapatka & Roland Eils

  4. Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin (BGFA), Ruhr University Bochum, Bochum, Germany

    Christiane B. Pierl, Sylvia Rabstein & Beate Pesch

  5. Department of Statistics, Universität Dortmund, Dortmund, Germany

    Silvia Selinski, Tina Mueller & Katja Ickstadt

  6. Institut für Arbeitsphysiologie an der Universität Dortmund, Dortmund, Germany

    Silvia Selinski & Hermann M. Bolt

  7. Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany

    Yon-Dschun Ko, Christian Baisch & Volker Harth

  8. Institute of Epidemiology, GSF-National Research Center for Environment and Health, Neuherberg, Germany

    Caren Vollmert & Thomas Illig

  9. Department of Mathematics, Universität Stuttgart, Stuttgart, Germany

    Jürgen Dippon

  10. University Tuebingen, Tuebingen, Germany

    Christina Justenhoven & Hiltrud Brauch

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  1. Christina Justenhoven
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  2. Ute Hamann
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  8. Tina Mueller
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Correspondence to Hiltrud Brauch.

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Justenhoven, C., Hamann, U., Schubert, F. et al. Breast cancer: a candidate gene approach across the estrogen metabolic pathway. Breast Cancer Res Treat 108, 137–149 (2008). https://doi.org/10.1007/s10549-007-9586-8

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