Abstract
Epidemiological studies have evaluated the association between catechol-O-methyltransferase (COMT) Val108/158Met polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. In order to derive a more precise estimation of the relationship, we performed this meta-analysis. Systematic searches of the PubMed and Medline databases were performed. A total of 41 studies including 25,627 cases and 34,222 controls were identified. Genotype distributions of COMT in the controls of all studies were in agreement with the Hardy–Weinberg equilibrium (HWE) except for three studies. When all 41 studies were pooled into the meta-analysis, there was no evidence for significant association between COMT Val108/158Met polymorphism and breast cancer risk (for Val/Met vs. Val/Val: OR = 0.99, 95% CI = 0.93–1.04; for Met/Met vs. Val/Val: OR = 0.96, 95% CI = 0.88–1.04; for dominant model: OR = 0.97, 95% CI = 0.92–1.03; for recessive model: OR = 0.97, 95% CI = 0.90–1.04). In the subgroup analyses by ethnicity, menopausal status, no significant associations were found in all genetic models. When sensitivity analyses were performed by excluding HWE-violating studies, all the results were not materially altered. In summary, the meta-analysis strongly suggests that COMT Val108/158Met polymorphism is not associated with increased breast cancer risk.
Similar content being viewed by others
References
Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 27(2):135–206
Männistö PT, Ulmanen I, Lundström K, Taskinen J, Tenhunen J, Tilgmann C, Kaakkola S (1992) Characteristics of calechol O-methyllransferase (COMT) and properties of selective COMT inhibitors. Prog Drug Res 39:291–350
Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, Ramanathan R, Cerny RL, Rogan EG (1997) Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci USA 94(20):10937–10942
Liehr JG (1997) Hormone-associated cancer: mechanistic similarities between human breast cancer and estrogen-induced kidney carcinogenesis in hamsters. Environ Health Perspect 105(suppl 3):565–569
Grossman MH, Emanuel BS, Budarf ML (1992) Chromosomal mapping of the human catechol-O-methyltransferase geneto 22q11.1–22q11.2. Genomics 12(4):822–825
Dawling S, Roodi N, Mernaugh RL, Wang X, Parl FF (2001) Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms. Cancer Res 61(18):6716–6722
Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6(3):243–250
Lavigne JA, Helzlsouer KJ, Huang HY, Strickland PT, Bell DA, Selmin O, Watson MA, Hoffman S, Comstock GW, Yager JD (1997) An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res 57(24):5493–5497
Millikan RC, Pittman GS, Tse CK, Duell E, Newman B, Savitz D, Moorman PG, Boissy RJ, Bell DA (1998) Catechol-O-methyltransferase and breast cancer risk. Carcinogenesis 19(11):1943–1947
Thompson PA, Shields PG, Freudenheim JL, Stone A, Vena JE, Marshall JR, Graham S, Laughlin R, Nemoto T, Kadlubar FF, Ambrosone CB (1998) Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk. Cancer Res 58(10):2107–2110
Huang CS, Chern HD, Chang KJ, Cheng CW, Hsu SM, Shen CY (1999) Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res 59(19):4870–4875
Bergman-Jungeström M, Wingren S (2001) Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women. Br J Cancer 85(6):859–862
Goodman JE, Lavigne JA, Wu K, Helzlsouer KJ, Strickland PT, Selhub J, Yager JD (2001) COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk. Carcinogenesis 22(10):1661–1665
Hamajima N, Matsuo K, Tajima K, Mizutani M, Iwata H, Iwase T, Miura S, Oya H, Obata Y (2001) Limited association between a catechol-O-methyltransferase (COMT) polymorphism and breast cancer risk in Japan. Int J Clin Oncol 6(1):13–18
Mitrunen K, Jourenkova N, Kataja V, Eskelinen M, Kosma VM, Benhamou S, Kang D, Vainio H, Uusitupa M, Hirvonen A (2001) Polymorphic catechol-O-methyltransferase gene and breast cancer risk. Cancer Epidemiol Biomarkers Prev 10(6):635–640
Yim DS, Parkb SK, Yoo KY, Yoon KS, Chung HH, Kang HL, Ahn SH, Noh DY, Choe KJ, Jang IJ, Shin SG, Strickland PT, Hirvonen A, Kang D (2001) Relationship between the Val108/158Met polymorphism of catechol O-methyl transferase and breast cancer. Pharmacogenetics 11(4):279–286
Kocabaş NA, Sardaş S, Cholerton S, Daly AK, Karakaya AE (2002) Cytochrome P450 CYP1B1 and catechol O-methyltransferase (COMT) genetic polymorphisms and breast cancer susceptibility in a Turkish population. Arch Toxicol 76(11):643–649
Comings DE, Gade-Andavolu R, Cone LA, Muhleman D, MacMurray JP (2003) A multigene test for the risk of sporadic breast carcinoma. Cancer 97(9):2160–2170
Tan W, Qi J, Xing DY, Miao XP, Pan KF, Zhang L, Lin DX (2003) Relation between single nucleotide polymorphism in estrogen-metabolizing genes COMT, CYP17 and breast cancer risk among Chinese women. Zhonghua Zhong Liu Za Zhi 25(5):453–456
Wedrén S, Rudqvist TR, Granath F, Weiderpass E, Ingelman-Sundberg M, Persson I, Magnusson C (2003) Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk. Carcinogenesis 24(4):681–687
Wu AH, Tseng CC, Van Den Berg D, Yu MC (2003) Tea intake, COMT genotype, and breast cancer in Asian-American women. Cancer Res 63(21):7526–7529
Ahsan H, Chen Y, Whittemore AS, Kibriya MG, Gurvich I, Senie RT, Santella RM (2004) A family-based genetic association study of variants in estrogen-metabolism genes COMT and CYP1B1 and breast cancer risk. Breast Cancer Res Treat 85(2):121–131
Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, Novik KL, Kelemen L, Ogata S, Pharoah PD, Easton DF, Day NE, Ponder BA (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945
Sazci A, Ergul E, Utkan NZ, Canturk NZ, Kaya G (2004) Catechol-O-methyltransferase Val 108/158 Met polymorphism in premenopausal breast cancer patients. Toxicology 204(2–3):197–202
Cheng TC, Chen ST, Huang CS, Fu YP, Yu JC, Cheng CW, Wu PE, Shen CY (2005) Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. Int J Cancer 113(3):345–353
Le Marchand L, Donlon T, Kolonel LN, Henderson BE, Wilkens LR (2005) Estrogen metabolism-related genes and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 14(8):1998–2003
Lin WY, Chou YC, Wu MH, Jeng YL, Huang HB, You SL, Chu TY, Chen CJ, Sun CA (2005) Polymorphic catechol-O-methyltransferase gene, duration of estrogen exposure, and breast cancer risk: a nested case-control study in Taiwan. Cancer Detect Prev 29(5):427–432
Lin SC, Chou YC, Wu MH, Wu CC, Lin WY, Yu CP, Yu JC, You SL, Chen CJ, Sun CA (2005) Genetic variants of myeloperoxidase and catechol-O-methyltransferase and breast cancer risk. Eur J Cancer Prev 14(3):257–261
Modugno F, Zmuda JM, Potter D, Cai C, Ziv E, Cummings SR, Stone KL, Morin PA, Greene D, Cauley JA (2005) Estrogen metabolizing polymorphisms and breast cancer risk among older white women. Breast Cancer Res Treat 93(3):261–270
Wen W, Cai Q, Shu XO, Cheng JR, Parl F, Pierce L, Gao YT, Zheng W (2005) Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis. Cancer Epidemiol Biomarkers Prev 14(2):329–335
Chang TW, Wang SM, Guo YL, Tsai PC, Huang CJ, Huang W (2006) Glutathione S-transferase polymorphisms associated with risk of breast cancer in southern Taiwan. Breast 15(6):754–761
Gallicchio L, Berndt SI, McSorley MA, Newschaffer CJ, Thuita LW, Argani P, Hoffman SC, Helzlsouer KJ (2006) Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease. BMC Cancer 6:173
Gaudet MM, Chanock S, Lissowska J, Berndt SI, Peplonska B, Brinton LA, Welch R, Yeager M, Bardin-Mikolajczak A, Garcia-Closas M (2006) Comprehensive assessment of genetic variation of catechol-O-methyltransferase and breast cancer risk. Cancer Res 66(19):9781–9785
Gaudet MM, Bensen JT, Schroeder J, Olshan AF, Terry MB, Eng SM, Teitelbaum SL, Britton JA, Lehman TA, Neugut AI, Ambrosone CB, Santella RM, Gammon MD (2006) Catechol-O-methyltransferase haplotypes and breast cancer among women on Long Island, New York. Breast Cancer Res Treat 99(2):235–240
Onay VU, Briollais L, Knight JA, Shi E, Wang Y, Wells S, Li H, Rajendram I, Andrulis IL, Ozcelik H (2006) SNP–SNP interactions in breast cancer susceptibility. BMC Cancer 6:114
Song CG, Hu Z, Yuan WT, Di GH, Shen ZZ, Huang W, Shao ZM (2006) Prevalence of Val108/158Met polymorphism in COMT gene on non-BRCA1/2 hereditary breast cancer. Zhonghua Wai Ke Za Zhi 44(19):1310–1313
Akisik E, Dalay N (2007) Functional polymorphism of thymidylate synthase, but not of the COMT and IL-1B genes, is associated with breast cancer. J Clin Lab Anal 21(2):97–102
Hu Z, Song CG, Lu JS, Luo JM, Shen ZZ, Huang W, Shao ZM (2007) A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives. J Cancer Res Clin Oncol 133(12):969–978
Ralph DA, Zhao LP, Aston CE, Manjeshwar S, Pugh TW, DeFreese DC, Gramling BA, Shimasaki CD, Jupe ER (2007) Age-specific association of steroid hormone pathway gene polymorphisms with breast cancer risk. Cancer 109(10):1940–1948
Takata Y, Maskarinec G, Le Marchand L (2007) Breast density and polymorphisms in genes coding for CYP1A2 and COMT: the Multiethnic Cohort. BMC Cancer 7:30
He C, Tamimi RM, Hankinson SE, Hunter DJ, Han J (2009) A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk. Breast Cancer Res Treat 113(3):585–594
Justenhoven C, Hamann U, Schubert F, Zapatka M, Pierl CB, Rabstein S, Selinski S, Mueller T, Ickstadt K, Gilbert M, Ko YD, Baisch C, Pesch B, Harth V, Bolt HM, Vollmert C, Illig T, Eils R, Dippon J, Brauch H (2008) Breast cancer: a candidate gene approach across the estrogen metabolic pathway. Breast Cancer Res Treat 108(1):137–149
Onay UV, Aaltonen K, Briollais L, Knight JA, Pabalan N, Kilpivaara O, Andrulis IL, Blomqvist C, Nevanlinna H, Ozcelik H (2008) Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk. BMC Cancer 8:6
Jakubowska A, Gronwald J, Menkiszak J, Górski B, Huzarski T, Byrski T, Tołoczko-Grabarek A, Gilbert M, Edler L, Zapatka M, Eils R, Lubiński J, Scott RJ, Hamann U (2009) BRCA1-associated breast and ovarian cancer risks in Poland: no association with commonly studied polymorphisms. Breast Cancer Res Treat. doi:10.1007/s10549-009-0390-5
The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk (2009) Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women. Breast Cancer Res Treat. doi:10.1007/s10549-009-0407-0
Reding KW, Weiss NS, Chen C, Li CI, Carlson CS, Wilkerson HW, Farin FM, Thummel KE, Daling JR, Malone KE (2009) Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk. Cancer Epidemiol Biomarkers Prev 18(5):1461–1467
Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Laird NM, Khuhaprema T, Brennan P, Boffetta P, Yoshida T (2009) Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women. Int J Cancer 125(4):837–843
Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10(1):101–129
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mao, C., Wang, XW., Qiu, LX. et al. Lack of association between catechol-O-methyltransferase Val108/158Met polymorphism and breast cancer risk: a meta-analysis of 25,627 cases and 34,222 controls. Breast Cancer Res Treat 121, 719–725 (2010). https://doi.org/10.1007/s10549-009-0650-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-009-0650-4