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Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms.

ABSTRACT: 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.

SUBMITTER: Ji Y

PROVIDER: S-EPMC2518124 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms.

Ji Yuan Y Olson Janet J Zhang Jianping J Hildebrandt Michelle M Wang Liewei L Ingle James J Fredericksen Zachary Z Sellers Thomas T Miller William W Dixon J Michael JM Brauch Hiltrud H Eichelbaum Michel M Justenhoven Christina C Hamann Ute U Ko Yon Y Brüning Thomas T Chang-Claude Jenny J Wang-Gohrke Shan S Schaid Daniel D Weinshilboum Richard R

Cancer research 20080701 14

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 stud ...[more]

PMID: 18632656

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Project description:BACKGROUND Existing research evidence indicates that breast cancer patients have different degrees of cognitive dysfunction after chemotherapy, and polymorphisms in 3 genes (catechol-O-methyltransferase, COMT; apolipoprotein E, APOE; and brain-derived neurotrophic factor, BDNF) have been associated with cognitive impairment. However, the role of these 3 gene polymorphisms in modulating cognitive impairment in breast cancer survivors with varying hormonal receptor expression is not clear at present. To explore the effects of genetic polymorphisms in BDNF, APOE, and COMT on the regulation of prospective memory impairments induced by chemotherapy in breast cancer patients with various expression levels of estrogen receptor (ER) and progesterone receptor (PR). MATERIAL AND METHODS A total of 232 patients with breast cancer (113 with ER-/PR- and 119 with ER+/PR+) were evaluated before and after chemotherapy for cognitive function, including prospective memory. Following previously published sequencing procedures, we assessed 6 single-nucleotide polymorphisms (SNPs), including BDNF (rs6265), APOE (rs429358, rs7412), and COMT (rs165599, rs4680, rs737865). RESULTS The patients showed poorer prospective memory scores after chemotherapy than before chemotherapy. Furthermore, the ER-/PR- group showed poorer event-based prospective memory (EBPM) scores than the ER+/PR+ group (z=-7.831, p<0.01) after chemotherapy. The patients with the COMT rs737865G/G genotype, compared with those with the A/A and A/G genotypes, showed a linear EBPM performance (ß=1.499, 95% confidence interval (CI)=1.017~2.211) and were less likely to have memory impairment. In contrast, APOE and BDNF polymorphisms did not influence cognitive performance. CONCLUSIONS The patterns of hormonal receptor expression may be related to prospective memory impairments induced by chemotherapy in breast cancer patients. Furthermore, the COMT polymorphism (rs737865) was linearly related to the extent of deficits in EBPM and may represent a potential genetic marker of risk for cognitive deficits triggered by chemotherapy in patients with breast cancer.

Project description:ObjectiveCatechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD.Approach and resultsWe examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar.ConclusionsCommon COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

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Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms.

Publications

Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms.

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