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 (COMTLL). 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 COMTHL and COMTLL genotypes were 1.30 [confidence interval (CI), 0.66–2.58] and 1.45 (CI, 0.69–3.07), respectively. Postmenopausal COMTLL 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 COMTLL 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 COMTLL 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.
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.