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

Yuan Ji, Janet E Olson, Jianping Zhang, Michelle Hildebrandt, Liewei M Wang, James Ingle, Zachary Fredericksen, Thomas Sellers, William Miller, J. Michael Dixon, Hiltrud Brauch, Michel Eichelbaum, Christina Justenhoven, Ute Hamann, Yon Ko, Thomas Brüning, Jenny Chang-Claude, Shan Wang-Gohrke, Daniel J Schaid, Richard M Weinshilboum

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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.

Original languageEnglish (US)
Pages (from-to)5997-6005
Number of pages9
JournalCancer Research
Volume68
Issue number14
DOIs
StatePublished - Jul 15 2008

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Catechol O-Methyltransferase
Genetic Polymorphisms
Risk Reduction Behavior
Breast Neoplasms
Single Nucleotide Polymorphism
Membranes
Catechol Estrogens
Confidence Intervals
Case-Control Studies
DNA
DNA-Binding Proteins
Methylation
Exons
Estrogens
Carcinogenesis
Up-Regulation
Alleles
Odds Ratio

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms. / Ji, Yuan; Olson, Janet E; Zhang, Jianping; Hildebrandt, Michelle; Wang, Liewei M; Ingle, James; Fredericksen, Zachary; Sellers, Thomas; Miller, William; Dixon, J. Michael; Brauch, Hiltrud; Eichelbaum, Michel; Justenhoven, Christina; Hamann, Ute; Ko, Yon; Brüning, Thomas; Chang-Claude, Jenny; Wang-Gohrke, Shan; Schaid, Daniel J; Weinshilboum, Richard M.

In: Cancer Research, Vol. 68, No. 14, 15.07.2008, p. 5997-6005.

Research output: Contribution to journalArticle

Ji, Y, Olson, JE, Zhang, J, Hildebrandt, M, Wang, LM, Ingle, J, Fredericksen, Z, Sellers, T, Miller, W, Dixon, JM, Brauch, H, Eichelbaum, M, Justenhoven, C, Hamann, U, Ko, Y, Brüning, T, Chang-Claude, J, Wang-Gohrke, S, Schaid, DJ & Weinshilboum, RM 2008, 'Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms', Cancer Research, vol. 68, no. 14, pp. 5997-6005. https://doi.org/10.1158/0008-5472.CAN-08-0043
Ji, Yuan ; Olson, Janet E ; Zhang, Jianping ; Hildebrandt, Michelle ; Wang, Liewei M ; Ingle, James ; Fredericksen, Zachary ; Sellers, Thomas ; Miller, William ; Dixon, J. Michael ; Brauch, Hiltrud ; Eichelbaum, Michel ; Justenhoven, Christina ; Hamann, Ute ; Ko, Yon ; Brüning, Thomas ; Chang-Claude, Jenny ; Wang-Gohrke, Shan ; Schaid, Daniel J ; Weinshilboum, Richard M. / Breast cancer risk reduction and membrane-bound catechol O-methyltransferase genetic polymorphisms. In: Cancer Research. 2008 ; Vol. 68, No. 14. pp. 5997-6005.
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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.",
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AU - Ingle, James

AU - Fredericksen, Zachary

AU - Sellers, Thomas

AU - Miller, William

AU - Dixon, J. Michael

AU - Brauch, Hiltrud

AU - Eichelbaum, Michel

AU - Justenhoven, Christina

AU - Hamann, Ute

AU - Ko, Yon

AU - Brüning, Thomas

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