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Breast Cancer Risk Reduction and Membrane-Bound Catechol O-Methyltransferase Genetic Polymorphisms

¹ Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, ² Department of Health Sciences Research, ³ Department of Oncology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota; ⁴ H. Lee Moffitt Cancer Center, Tampa, Florida; ⁵ Western General Hospital, Edinburgh, Scotland; ⁶ Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, and Tübingen Universität, Tübingen, Germany; ⁷ German Cancer Research Center, Heidelberg, Germany; ⁸ Johanniter Hospital Bonn, Bonn, Germany; ⁹ Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin, Ruhr Universität Bochum, Bochum, Germany; and ¹⁰ Women's Hospital of the University of Ulm, Ulm, Germany

Requests for reprints: Richard M. Weinshilboum, Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-2246; Fax: 507-284-4455; E-mail: Weinshilboum.Richard{at}mayo.edu.

Key Words: Catechol-O-methyltransferase • COMT • MB-COMT • S-COMT • breast cancer risk • genetic polymorphism • SNPs • functional genomics

Catechol O-methyltransferase (COMT)-catalyzed methylation of catecholestrogens has been proposed to play a protective role in estrogen-induced genotoxic carcinogenesis. We have taken a comprehensive approach to test the hypothesis that genetic variation in COMT might influence breast cancer risk. Fifteen COMT single nucleotide polymorphisms (SNPs) selected on the basis of in-depth resequencing of the COMT gene were genotyped in 1,482 DNA samples from a Mayo Clinic breast cancer case control study. Two common SNPs in the distal promoter for membrane-bound (MB) COMT, rs2020917 and rs737865, were associated with breast cancer risk reduction in premenopausal women in the Mayo Clinic study, with allele-specific odds ratios (OR) of 0.70 [95% confidence interval (CI), 0.52–0.95] and 0.68 (95% CI, 0.51–0.92), respectively. These two SNPs were then subjected to functional genomic analysis and were genotyped in an additional 3,683 DNA samples from two independent case control studies (GENICA and GESBC). Functional genomic experiments showed that these SNPs could up-regulate transcription and that they altered DNA-protein binding patterns. Furthermore, substrate kinetic and exon array analyses suggested a role for MB-COMT in catecholestrogen inactivation. The GENICA results were similar to the Mayo case control observations, with ORs of 0.85 (95% CI, 0.72–1.00) and 0.85 (95% CI, 0.72–1.01) for the two SNPs. No significant effect was observed in the GESBC study. These studies showed that two SNPs in the COMT distal promoter were associated with breast cancer risk reduction in two of three case control studies, compatible with the results of functional genomic experiments, suggesting a role for MB-COMT in breast cancer risk. [Cancer Res 2008;68(14):5997–6005]