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Val158Met Polymorphism in Catechol-O-methyltransferase Gene Associated with Risk Factors for Breast Cancer¹

Division of Epidemiology and Statistics, Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada [C-C. H., D. T., N. F. B.]; Cancer Prevention Laboratory, Colorado State University, Fort Collins, Colorado 80523-1173 [H. J. T.]; The Hormel Institute, University of Minnesota, Northeast Austin, Minnesota 55912 [C. J.]; Medical Imaging Research, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, M4N 3M5 Canada; [M. Y.]; and British Columbia Research Institute for Children’s and Women’s Health, Vancouver, British Columbia, Canada [G. L. H.]

Extensive mammographic density is heritable, strongly associated with increased breast cancer risk, and is influenced by sex hormone exposure. In a cross-sectional study of 181 pre- and 171 postmenopausal women without breast cancer, we examined the relationship of a functional polymorphism in catechol-O-methyltransferase (COMT; VALMET) to mammographic density and other risk factors for breast cancer. We hypothesized that individuals who inherited the low-activity form of COMT (COMT*2 allele) would have higher levels of breast density, presumably because of reduced inactivation/ detoxification of catecholestrogens. Subjects were recruited across five categories of breast density. Risk factor information, anthropometric measures, and blood samples were obtained; sex hormone and growth factor levels were measured, and COMT genotypes determined. Mammograms were digitized and measured using a computer-assisted method. After adjustment for age and ethnicity, among pre- but not postmenopausal subjects, each low-activity COMT*2 allele was associated with lower levels of percentage breast density. The statistical significance of this association was lost after further adjustment for serum growth factors [growth hormone, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3)], hormones [follicle-stimulating hormone (FSH) and progesterone], and body size (body mass index and waist:hip ratio). The low-activity COMT*2 allele was also associated, after adjustment for age and ethnicity in premenopausal women, with lower serum levels of IGF-1, higher levels of FSH and progesterone, and with a larger waist:hip ratio, body mass index, and subscapular skinfold. After adjustment for body size, the associations of genotype with IGFBP-3 and FSH were no longer significant. These findings indicate that COMT genotype is associated with several risk factors for breast cancer and suggest that the low-activity COMT*2 allele is associated with a reduced risk of breast cancer among premenopausal women.

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