Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk
Sara Wedrén1,5,
Tove Rylander Rudqvist2,
Fredrik Granath1,
Elisabete Weiderpass1,3,
Magnus Ingelman-Sundberg2,
Ingemar Persson1,4 and
Cecilia Magnusson1
1 Department of Medical Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
2 Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
3 International Agency for Research on Cancer, Lyon, France
4 Swedish Medical Products Agency, Uppsala, Sweden
5 To whom correspondence should be addressed Email: sara.wedren{at}mep.ki.se
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Abstract
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Estrogen is involved in breast carcinogenesis. Hypotheses have been raised that its effect is modified by enzymes such as catechol-O-methyltransferase (COMT) that deactivate potentially genotoxic estrogen metabolites. We have investigated the association between the functional genetic Val108/158Met polymorphism in COMT and breast cancer risk in a large population-based casecontrol study performed in the genetically homogeneous Swedish population. We determined COMT genotype in 1534 women with invasive breast cancer and in 1504 control women and calculated odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models. There was no overall association between COMT genotype and breast cancer risk. However, the L allele was associated with an increased risk for lobular breast cancer, with OR 2.0 (95% CI 1.23.5) for HL and 1.7 (95% CI 0.93.0) for LL. In exploratory subset analyses, we found no statistically significant interaction, but some indication of a positive association between HL and LL genotypes and breast cancer among women with diabetes mellitus and a negative association among nulliparous women. Based on our findings, COMT activity alone does not seem to play a major role in breast carcinogenesis, but may be of importance in certain histotypes or in conjunction with other exposures.
Abbreviations: BMI, body mass index; CI, confidence interval; COMT, catechol-O-methyltransferase; DASH, dynamic allele-specific hybridization; NIDDM, non-insulin-dependent diabetes; OR, odds ratios; SNP, single nucleotide polymorphism.
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Introduction
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Estrogens are known to be central in breast carcinogenesis. Estrogens induce proliferation but may also initiate cancer via metabolic activation to potentially carcinogenic catechol estrogen metabolites (1). The impact of this latter mechanism in human breast carcinogenesis remains undefined.
Catechol-O-methyltransferase (COMT) is a phase II enzyme that deactivates catechol estrogens into non-genotoxic methyl ethers that can be easily excreted by the body. In COMT there is a single nucleotide polymorphism (SNP) that results in an amino acid exchange from valine to methionine at codon 108/158 in the membrane-bound/cytoplasmic protein (2). The Val108/158Met allele encodes a thermolabile variant of the enzyme that in homozygotes confers an about 2- to 4-fold lower catalytic activity (3,4). Heterozygous individuals have intermediate and homozygous wild-type have high enzyme activity. Carrying low activity COMT alleles is hypothesized to be associated with an increased risk for breast cancer through accumulation of genotoxic metabolites (5). However, results from epidemiological studies (Table I) have been inconsistent. In an attempt to shed further light on the issue of whether COMT genotype has an influence on breast cancer risk we have performed a large casecontrol study in a genetically homogeneous population with extensive information about lifestyle and tumor characteristics.
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Materials and methods
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Founding study
This nation wide casecontrol study encompassed all incident cases of primary breast cancer among women 50 and 74 years of age resident in Sweden between October 1993 and March 1995 (6). Breast cancer patients were identified at diagnosis through a notification system organized within the six Swedish regional cancer registries, to which reporting of all cancers is mandatory. Controls were randomly selected in 5 year age strata (to match the expected age frequency distribution among the cases) from the Swedish Registry of Total Population.
Cases were asked to participate in the study by their respective physicians. Only when patients consented were we notified of their identity and address and they were sent a mailed questionnaire asking for detailed information about intake of menopausal hormones and oral contraceptives, weight, height, reproductive history, medical history and other lifestyle factors. Controls were contacted with the questionnaire directly by us. Eighty-four percent of eligible cases (n = 3345) and 82% of the controls (n = 3454) subsequently completed the questionnaire. Among these controls, 455 who failed to return the mailed questionnaire were interviewed by telephone. Results from the founding study have been published (610). Information about tumor type, size and stage has been collected from medical records in an ongoing follow-up study of all breast cancer cases.
Present study
We randomly selected 1500 women with invasive breast cancer and 1500 age frequency matched controls among post-menopausal participants without any previous malignancy (except cervix carcinoma in situ or non-melanoma skin cancer) in the founding study. In order to increase statistical power in subgroup analyses, we additionally selected all remaining women (cases and controls) who had used menopausal hormones (either medium potency estrogen treatment only or medium potency estrogen in combination with progestin) for at least 4 years (191 cases and 108 controls) and all women with self-reported diabetes mellitus (104 cases and 110 controls). In total, 1801 cases and 1712 controls were selected.
Collection of biological samples
We contacted all selected living women by mail and those who gave informed consent received a blood sampling kit by mail. Whole blood samples were drawn at a primary health care facility close to the woman's home and sent to us by standard mail. A majority of the samples arrived at our department within 1 day from blood draw. All blood samples were immediately stored at -20°C. Breast cancer cases who did not want to donate a blood sample were asked whether they consented to our use of archived paraffin-embedded tissue samples taken at breast cancer surgery. We also attempted to retrieve archived tissue samples from all deceased breast cancer cases. Samples were anonymized and subsequently transferred to the laboratories. We obtained blood samples or archived tissue samples for 1322 and 247 breast cancer patients, respectively, and blood samples from 1272 control women. Some controls from the founding study that were not selected for this study donated blood for a parallel study about endometrial cancer. As these women originated from the same source population and fulfilled all inclusion criteria, they could potentially also serve as controls.
We isolated DNA from 3 ml whole blood using a Wizard Genomic DNA Purification Kit (Promega, Madison, WI) according to the manufacturer's instructions. From non-malignant cells in paraffin-embedded tissue, we extracted DNA using a standard phenol/chloroform/isoamyl alcohol protocol (11).
Genetic analyses
We used two methods for COMT genotyping: multiplex fluorescent solid phase minisequencing (hereafter called minisequencing) (12) and dynamic allele-specific hybridization (DASH) (13). We validated results from the above two methods with a restriction fragment length polymorphism method and through replicates. All PCRs were performed on a Perkin Elmer GeneAmp 9700 system and the presence of amplicons was checked on agarose gels. The multiplex PCR that we used for minisequencing was sensitive to DNA quality. In order to increase genotyping success to include suboptimal samples we switched from minisequencing to DASH. DASH is a robust high throughput method that allows separate PCR reactions with retained efficiency.
Minisequencing
Five SNPs were analyzed simultaneously, one in the COMT gene, reported here, and four in other genes, reported elsewhere. SNPs are detected by specific extension with single fluorescein-labeled (NEN/DuPont, Boston, MA) ddNTPs of a primer that anneals immediately adjacent to the variable site. To minimize pipetting steps, we used an AutoLoad kit (Amersham, Pharmacia Biotech, Uppsala, Sweden) where PCR products are immobilized on streptavidin-coated comb-shaped manifold supports. The primer sequences are shown in Table II. The 25 µl multiplex PCR mix contained 100 ng DNA, 20 mM TrisHCl pH 8.4, 50 mM KCl, 0.2 mM each dNTP, 1.8 mM MgCl2, 10% DMSO, 0.625 U Platinum® Taq polymerase (Life Technologies, Rockville, MD) and 0.25 µM primer. The initial denaturation was performed at 95°C for 2 min, followed by 35 cycles each consisting of denaturation at 95°C for 15 s, annealing at 56°C and extension at 72°C for 1 min, followed by a final extension at 72°C for 7 min. An aliquot of 6 µl biotinylated PCR product was immobilized on streptavidin-coated sequencing combs. The minisequencing procedure was performed as described by Pastinen et al. (12), with the following modifications; the four minisequencing reaction mixtures contained 26 mM TrisHCl pH 9.5, 6.5 mM MgCl2, 2 µM each sequencing primer (Table II), 0.05 µM F-ddGTP or 0.25 µM F-ddATP or 0.5 µM F-ddCTP or 0.5 µM F-ddUTP, 0.5 µM the three other unlabeled ddNTPs and 0.26 U Thermo Sequenase DNA polymerase (Amersham Pharmacia Biotech). The extended primers where analyzed on an ALF DNA-Autosequencer (Amersham, Pharmacia Biotech) and the chromatograms were interpreted by direct visual inspection.
DASH
The PCR mix contained 10 ng DNA, 15 mM TrisHCl pH 8.0, 50 mM KCl, 0.12 µM biotinylated 5'-primer, 0.6 µM 3'-primer (Table II), 0.2 mM each dNTP (HPLC purified; Interactiva GmbH, Ulm, Germany), 3.0 mM MgCl2, 5% DMSO, 0.6 U AmpliTaq GOLD polymerase (Applied Biosystems, Foster City, CA) in a total volume of 25 µl. The initial denaturation was performed at 95°C for 10 min, followed by 38 cycles each consisting of denaturation at 95°C for 15 s, annealing at 60°C for 30 s, followed by a final extension at 72°C for 4 min. DASH assays were performed as described by Prince et al. (13) and genotypes were scored from fluorescence curves as described by Howell et al. (14).
RFLP analysis
As reference analysis, the two COMT alleles were identified with a PCR-based restriction fragment length polymorphism method according to Lachman et al. (2) with the exception that the PCR was performed with the same primers and identical conditions as used in the multiplex PCR (Table II). An aliquot of 8 µl of the PCR product was digested with NlaIII (New England Biolabs) for 3 h at 37°C. The digested PCR products were visualized on a 4% low melting point agarose gel.
Statistical analyses
We checked the assumption of a HardyWeinberg equilibrium among the controls using standard
2 statistics. As it is known that COMT polymorphism has a co-dominant mode of action (15), we considered each genotype to carry its own associated risk. We assessed potential association between genotype and known or suspected risk factors for breast cancer among controls by
2 statistics. We calculated odds ratios (OR) and 95% confidence intervals (CI) from conditional logistic regression models using the maximum likelihood method. Models were conditioned on age group and on sampling category to ensure that age-associated non-participation or over-sampling of long-term menopausal hormone users and diabetics did not introduce bias. The potential for confounding by other known breast cancer risk factors is doubtful since these factors may lie in the causal pathway between the studied genetic variation and breast cancer.
We investigated interaction between COMT genotype and duration of menopausal estrogen treatment use and diabetes mellitus by performing separate analyses over strata of these exposures. We could not estimate the joint effect of genotype and hormone use or diabetes mellitus due to our sampling scheme. Interactions with these variables were tested through a Wald statistic that evaluates whether the coefficients for genotype effect in successive strata of the risk factor in question are equal to 0. We studied interaction with body mass index (BMI), parity and family history in a model evaluating the joint effects of the risk factor and genotype. To test the interactions formally, these models were compared with models including only the main effects. The likelihood ratio test was used to generate a P value. In secondary analyses, we also explored possible interaction between genotype and other exposures.
We performed all analyses using SAS system PHREG procedure release 8.01 (SAS Institute Inc., Cary, NC).
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Results
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We successfully genotyped 1534 breast cancer cases and 1252 controls. In the following statistical analysis, we included 252 additional genotyped controls from the same source population that were genotyped for a parallel endometrial cancer study (see above). Thus, the total number of controls included was 1504.
Selected characteristics of the study participants by genotype are shown in Table III. The genotype frequencies among the controls were in accordance with a HardyWeinberg equilibrium (P = 0.83). Among the controls, there were statistically significant associations between COMT genotype and parity (0, 1, 2 or >2 childbirths, P = 0.04) and between genotype and intake of brassica vegetables (<1, 13 or >3 times per week, P = 0.03), but the associations did not follow any doseresponse or other plausible pattern. Remaining potential breast cancer risk factors did not co-vary with COMT genotype among controls (data not shown). When introduced into the logistic model none of the variables changed the estimates of association between genotype and breast cancer. Thus, the final model contained only COMT genotype, but the analyses were conditioned on the variables used for sampling, i.e. use of menopausal estrogen alone (never, <4 years or
4 years), use of menopausal estrogen in combination with progestin (never, <4 years or
4 years) and diabetes mellitus (yes or no).
We found no relation between COMT genotype and breast cancer risk overall (Table IV). Yet, the low activity allele appeared associated with an increased risk for lobular type breast cancer; OR 1.8 (95% CI 1.13.1) for HL and 1.6 for LL (95% CI 0.92.8) (Table IV). There were no associations between COMT genotype and tumor size or tumor stage at diagnosis (data not shown).
Results of exploratory stratified analyses are shown in Tables V and VI. In Table V we present analyses stratified by menopausal hormone use and diabetes mellitus using women with the HH genotype as reference. Our data do not speak in favor of an interaction between genotype and menopausal hormone use. Among HL women, short-term use of any menopausal hormones was negatively associated and long-term use was positively (and non-significantly) associated with breast cancer (Table V). The contrast between short- and long-term hormone users with the HL genotype conferred a P for interaction of 0.06, but no difference in the effect of genotype by duration of use was seen among LL women. There was a suggestion that COMT genotype was associated with breast cancer risk among women with diabetes mellitus but not among those without diabetes (P for interaction = 0.07) (Table V).
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Table V. Analyses of the association between COMT genotype and breast cancer risk stratified by use of menopausal hormones and diabetes mellitus with OR and 95% CI
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Table VI. Analyses of the joint effect of COMT genotype and BMI, parity and family history on breast cancer risk with odds ratios (OR) and 95% confidence intervals (CI)
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In Table VI we present associations between breast cancer and jointly genotype and either BMI, parity or first degree family history of breast cancer. Established associations between breast cancer and BMI, parity and family history did not appear to vary substantially with COMT genotype (Table VI). It could be noted, however, that among nulliparous women, HL and LL genotypes seemed to be negatively associated with breast cancer. No suggestions of a geneenvironment interaction emerged in secondary analyses stratified by other known or suspected risk factors (data not shown).
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Discussion
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There was no overall association between COMT genotype and breast cancer risk. However, genotypes conferring lowered COMT activity were associated with an increased risk for lobular breast cancer. Similarly, HL or LL women with diabetes mellitus had a 2-fold increased risk for breast cancer, whereas there was no association among non-diabetics.
There is evidence that the connection between estrogen and breast cancer is stronger for the lobular histotype (16,17). Since low COMT activity could entail relatively higher levels of estrogens, the finding of an effect of COMT genotype on risk for lobular but not ductal breast cancer is biologically plausible. We did not find any support for our a priori hypothesis that COMT genotype should be more important among long-term users of menopausal hormones. Our finding of an apparently halved breast cancer risk among L allele heterozygotes with short-term use of combined estrogen/progestin treatment is difficult to interpret biologically and may be due to chance. We found an increased risk among women with the HL or LL genotypes and diabetes mellitus (most commonly non-insulin-dependent diabetes, NIDDM). NIDDM involves hyperinsulinemia and higher levels of insulin-like growth factors, which may stimulate proliferation of the breast epithelium (18) and thus render it more susceptible to DNA damage. Our finding of an increased risk for breast cancer among diabetics is also consistent with a recent finding that hyperglycemia reduces COMT activity (19), which would further enhance exposure of the breast epithelium to estrogens and their genotoxic metabolites. Lastly, our data suggested that the COMT L allele is protective among nulliparous women, a finding that needs corroboration and biological explanation.
This is the largest study of the relation between COMT genotype and breast cancer published to date. Given our sample size and 5% significance level, we had 83% statistical power to detect a relative risk for breast cancer of 1.4 or higher for the LL genotype in overall analyses. Previously collected information about lifestyle factors and medication allowed us to explore their possible interaction with genotype. This may be vital since it is conceivable that an effect of genotype does not manifest itself in the absence of other exposures. Exposure information was collected retrospectively. However, in order for differential recall to influence our results, women would systematically have to answer according to genotype. COMT genotype has been linked to personality aspects such as schizophrenia (20) and prefrontal cognition (21), but these associations are weak and we believe that genotype guided recall or non-participation is unlikely. We did not have access to tumor biomarker characteristics and thus could not further define, beyond histologic type, distinct sub-types of breast cancer that may have distinct etiologies, as has been suggested by, among others, Thompson and Ambrosone (22). Most of our subgroup findings were associations between HL genotype and breast cancer. There are no data to indicate that those with intermediate COMT activity (i.e. the heterozygotes) should biochemically be at higher risk for disease. Rather, one would expect clear allele doseresponse relations in the results. In the LL group, however, smaller sample size leads to more chance fluctuation and decreased power. Obviously, our results should be interpreted with caution because of the multiple tests performed and the lack of persuasive allele doseresponse patterns.
Haiman and colleagues recently showed that, compared with COMT HH women, those with the LL genotype had higher mammographic density, an established risk factor for breast cancer (23). Casecontrol studies of the association between COMT genotype and breast cancer have, all the same, been inconsistent (Table I). Initially, Lavigne and colleagues found indications of a moderately increased risk, with an allele doseresponse pattern, for post-menopausal breast cancer for women with the HL or LL genotypes (24). Subsequently, investigators have found the L allele to confer protection against post-menopausal breast cancer (25), no altered risk (26,27) or increased risk among heterozygotes and protection among homozygotes (28,29). The conflicting previous results may indicate that COMT polymorphism has no influence on breast cancer risk and may represent chance findings. There are, however, alternative explanations. If COMT variation only reveals itself phenotypically in the presence of other exposures, diverging results may be due to varying prevalence of these exposures across different populations.
Several of the above studies found increased or decreased risks with COMT genotype in subgroups defined by one or combinations of other risk factors, such as menopausal status (2427), BMI (24,25,27), physical activity (26), folate or homocysteine levels (30), hormone use (27,31) and glutathione S-transferase activity (31). However, since the power for subgroup analyses was generally low, the patterns inconsistent and the multiple comparisons problem evident, these results have to be carefully interpreted. We did not replicate the finding by Matsui and colleagues (32) of an association between the L allele and more advanced clinical stage of breast cancer or a higher degree of lymph node metastasis. To our knowledge, a connection between COMT polymorphism and lobular breast cancer, as indicated in this study, has not been reported before.
Based on our findings, COMT activity alone does not seem to play a major role in breast carcinogenesis but may be of importance in certain histotypes or in conjunction with other exposures.
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Acknowledgments
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We are grateful to all women who have participated in this study, in particular those who took the effort to supply us with a blood sample. We are also indebted to Anna Christensson and Boel Bissmarck for invaluable assistance in blood sample collection, to Susanne Ahlberg for skillful technical assistance with the genotyping, and to Hans-Olov Adami for all-embracing guidance. Furthermore, we wish to express our gratitude to primary health care centers and pathology departments all over Sweden for their cooperation. This study was supported by the National Institutes of Health, grant number R03 CA83114, and by the Swedish Cancer Society, grant number 4112-B99-02XBB.
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Received August 30, 2002;
revised January 13, 2003;
accepted February 11, 2003.