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An Association between the Allele Coding for a Low Activity Variant of Catechol-O-methyltransferase and the Risk for Breast Cancer¹

Department of Environmental Health Sciences [J. A. L., J. D. Y.], Divisions of Toxicological Sciences and Environmental and Occupational Health [P. T. S.], and Department of Epidemiology [K. J. H., H-Y. H., S. H., G. W. C.], The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205-2179, and Genetic Risk Group, Laboratory of Computational Biology and Risk Assessment, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [D. A. B., O. S., M. A. W.]

Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT^LL). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT^HL and COMT^LL genotypes were 1.30 [confidence interval (CI), 0.66–2.58] and 1.45 (CI, 0.69–3.07), respectively. Postmenopausal COMT^LL women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93–5.11]. The association of COMT^LL with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m² (OR, 3.58; CI, 1.07–11.98). When COMT^LL was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.

¹ This research was supported by USPHS/NIH Grants RO3 CA70655 (to J. D. Y.), T32 ES07141 (to J. A. L.), RO1 CA62988 (to K. J. H.), and Career Research Award RO1 HL21670 (to G. W. C.) and Grant DAMD17-94-J-4265 from the Department of Defense (to K. J. H.). Shared instrumentation was supported by Center Grant P30 ES03819.

² To whom requests for reprints should be addressed, at The Johns Hopkins School of Hygiene and Public Health, Department of Environmental Health Sciences, Division of Toxicological Sciences, Room 7032, 615 North Wolfe Street, Baltimore, MD 21205-2179. Phone: (410) 955-4782; Fax: (410) 955-0116; E-mail: jyager@jhsph.edu.

Received 9/10/97. Accepted 10/28/97.

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