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[Cancer Research 66, 9781-9785, October 1, 2006]
© 2006 American Association for Cancer Research

Epidemiology and Prevention

Comprehensive Assessment of Genetic Variation of Catechol-O-Methyltransferase and Breast Cancer Risk

Mia M. Gaudet1, Stephen Chanock1,2, Jolanta Lissowska1,3, Sonja I. Berndt1, Beata Peplonska4, Louise A. Brinton1, Robert Welch2, Meredith Yeager2, Alicja Bardin-Mikolajczak3 and Montserrat Garcia-Closas1

1 Division of Cancer Epidemiology and Genetics and 2 Core Genotype Facility at the Advanced Technology Center, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; 3 Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland; and 4 Department of Occupational and Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland

Requests for reprints: Mia M. Gaudet, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS/7055, Rockville, MD 20852. Phone: 301-435-4725; Fax: 301-402-0916; E-mail: gaudetm{at}mail.nih.gov.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Because catechol-O-methyltransferase (COMT) catalyzes the addition of methyl groups to stabilize catechol estrogens that may induce DNA damage, genetic variants could influence breast cancer risk. To comprehensively characterize genetic variation in this gene, we selected haplotype-tagging single nucleotide polymorphisms (htSNP) in COMT. A total of 11 htSNPs (including COMT Val158Met) were selected based on the resequencing and dense genotyping approach of the Breast and Prostate Cancer Cohort Consortium. htSNPs were genotyped in a population-based, case-control study in Poland (1,995 cases and 2,296 controls). Individual SNPs were not significantly associated with risk. Haplotypes were estimated using the expectation-maximization algorithm. Overall differences in the haplotype distribution between cases and controls were assessed using a global score test. The TGAG haplotype (frequent in 4.3% of controls), in a linkage disequilibrium (LD) block that included the 3' untranslated region (UTR) of COMT, was associated with breast cancer risk (odds ratio, 1.29; 95% confidence interval, 1.06-1.58) compared with the most common haplotype TGAA; however, the global test for haplotype associations was not significant (P = 0.09). Haplotypes in another LD block, which included COMT Val158Met, were not associated with breast cancer risk (global P = 0.76). Haplotype-breast cancer risk associations were not significantly modified by hormonally related risk factors, family history of breast cancer, or tumor characteristics. In summary, our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3' UTR of COMT needs to be confirmed in independent study populations. (Cancer Res 2006; 66(19): 9781-5)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Catechol-O-methyltransferase (COMT) catalyzes the addition of a methyl group to reactive catechol estrogens to convert them into stable methyloxyestrogen conjugates. The conversion of catechol estrogens to stable conjugates may be important in preventing breast cancer, because metabolites of catechol estrogens have the potential to induce oxidative DNA damage and form DNA adducts. The COMT gene, located on chromosome 22q11, encode for two splice variants: one yielding a 271-amino-acid membrane-bound enzyme (COMT-MB), and the other, a 221-amino-acid soluble enzyme (COMT-S), which resides in the cytoplasm. Separate promoters, P2 and P1, regulate the transcription of COMT-MB and COMT-S, respectively. Both enzymes have similar functions and are expressed in a range of tissues, including breast; however, the soluble form may have greater affinity for catechol moieties (1) and could be more active in non–brain tissues (2).

In the past, there has been considerable interest in a single nucleotide polymorphism (SNP) in codon 158 that results in a valine to methionine amino acid substitution (rs4680), known to alter enzyme thermolability (1) and lower methylation activity (3, 4) in vitro. A recent meta-analysis of 8,286 cases and 7,344 controls found no evidence for an association with breast cancer risk: odds ratio (OR) 0.96 [95% confidence interval (95% CI), 0.83-1.12] and OR 0.89 (95% CI, 0.76-1.05) for carriers of one or two of variant alleles, respectively, compared with the common genotype (5). However, additional genetic variation in COMT not captured by this SNP could be related to risk (6, 7). Thus, to comprehensively assess common genetic variation within and around COMT, we assayed haplotype-tagging (ht)SNPs, and examined them in relation to breast cancer risk in a population-based, case-control study of Polish women.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study population. A large, population-based case-control study was conducted among women ages 20 to 74 years residing in two Polish cities, Warsaw and Lodz, from 2000 to 2003 (8). Eligible cases were newly diagnosed with either histologically or cytologically confirmed in situ or invasive breast cancer, and were identified through a rapid identification system and cancer registries to ensure complete case ascertainment. Controls with no history of breast cancer were frequency-matched to cases by city and age, and were randomly selected through the Polish Electronic System, a database of all residents. Institutional Review Board approval was obtained from all participating institutions, and signed informed consent was obtained for all respondents.

A total of 2,386 cases (79% of the 3,037 eligible cases identified) and 2,502 controls (69% of the 3,639 eligible controls identified) provided a personal interview on known and suspected risk factors. The primary reasons for nonparticipation of eligible cases and controls, respectively, were refusal (18% and 24%), inability to locate the individual (2% and 6%), death (<0.5%, <0.5%), and other reasons (<0.5%, <0.5%). Trained nurses also collected venous blood samples from 1,995 cases (84% of participating cases) and 2,296 controls (94% of participating controls). Genomic DNA was isolated from buffy coats by the Autopure LS DNA Purification System (Gentra Systems, Inc., Minneapolis, MN).

htSNP selection. Common genetic variation (minor allele frequency >5% in European Americans) was extensively assessed 19.3 kb upstream of the transcription start site for COMT-MB, through all exons and introns (including COMT-S), and ending 12.6 kb downstream of the mutual stop codon (59.1 kb total) using a two-step approach conducted by the Breast and Prostate Cohort Consortium (BPC3; ref. 9). First, a dense survey of common SNPs was conducted using the public database, dbSNP.5 Given the close proximity of the adjacent genes thioredoxin reductase 2 (TXNRD2) and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), some SNPs in these genes were also included in our analysis. In the second step, undertaken to identify unknown SNPs, a resequence analysis of COMT was done in 190 subjects with advanced breast or prostate cancer in the multiethnic cohort (9). A total of 28 SNPs (Supplementary Table S1) were identified and selected through these two approaches and were spaced roughly every 1 to 2 kb. Genotyping assays were developed and validated by resequencing analysis in the SNP500 cancer set (n = 102; ref. 10). These SNPs were then genotyped in a multiethnic panel of 733 individuals (referred to the BPC3 haplotyping panel; ref. 9) to assess allele frequencies and impute haplotypes, using an expectation-maximization algorithm (11). Haplotype structure was confirmed among 12 three-generation CEPH family pedigrees. A minimum set of 11 htSNPs (Table 1 ) were selected using the TagSNPs program (12).6 In the BPC3 haplotyping panel, four linkage disequilibrium (LD) blocks were observed using Gabriel's algorithm (13). These four LD blocks were combined into two LD blocks (blocks 1-3 were combined and block 4 remained unchanged) to improve statistical efficiency without losing the predictive power of the htSNPs. htSNPs for the two LD blocks defined in our study captured a majority of common haplotype diversity among European Americans (RH2 for block 1 = 0.86, RH2 for block 2 = 0.99).


View this table:
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  		Table 1. Age- and center-adjusted ORs and 95% CIs for the association between COMT htSNPs and breast cancer in a case-control study of Polish women (1,995 cases and 2,296 controls)

 
Genotyping. In the Polish study, genotype analysis was done in 1,995 cases and 2,296 controls. A total of 100 duplicate DNA pairs were >98% concordant for each SNP with the exception of rs3810595, for which 93% of the pairs were concordant (six of seven discordant pairs were due to loss of heterozygosity). DNA plates also contained 41 replicate samples from two unidentified donors. These replicates were >98% concordant for all SNPs with the exception of rs3810595, 93% replicates of which were concordant. Genotypes were called for >98% of all SNPs with the exception of rs4485648 (97% complete) and rs9332377 (96% complete). Genotypes were determined using individual TaqMan assays (Applied Biosystems, Forest City, CA). Assay descriptions can be found online (14).7 Genotype frequencies for all loci were in Hardy-Weinberg equilibrium among controls.

Statistical analyses. Unconditional logistic regression models were used to estimate ORs and 95% CIs, adjusted for the matching factors (age and city), for the association between individual SNPs and breast cancer, using STATA (version 8.2). Genotypes were evaluated using indicator variables. We assumed an additive mode of inheritance to calculate the P value for trend of individual SNPs.

Haploview8 was used to assess pairwise LD in Polish controls (Fig. 1 ). Haplotype analyses were conducted using the two LD block structures used to select htSNPs in the BPC3 haplotyping panel. We also examined alternate definitions based on the LD structure among Polish controls, which included four LD blocks (using a solid spline definition with D' < 0.80) that were comparable with the BPC3 data. Haplotype frequencies, as well as ORs and 95% CIs, were estimated using HaploStats (version 1.2.1; ref. 15), assuming an additive model. A global score statistic, adjusted for the matching factors, was used to evaluate the overall difference in haplotype frequencies between cases and controls (15).


Figure 1
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  		Figure 1. Gene map and LD plot of COMT htSNPs in Polish control women. LD strength between SNPs, as indicated by the color scheme, was measured using a combination of the statistic D' and the LOD score (dark shade, D' = 1 and LOD score ≥2; lighter shades, D' < 1 and LOD score <2). Numbers in squares are D' values.

 
We examined modification of individual SNP and haplotype results by self-reported menopausal status, history of a first-degree relative diagnosed with breast cancer, parity, age at first full-term birth, age at menopause, age at menarche, obesity at reference date among postmenopausal women, invasiveness (in situ, invasive), tumor size, nodal status, and estrogen and progesterone tumor receptor status. Hormone receptor status was determined by immunohistochemical assays (91% of cases) or by biochemical methods. Among women with genotyping data, 910 (66%) cases were diagnosed with estrogen receptor–positive tumors, and 760 (56%) cases were diagnosed with progesterone receptor–positive tumors.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Our Polish study population was composed of mostly postmenopausal women (69% of controls). Established breast cancer risk factors had associations with breast cancer that were in the expected direction and magnitude (8). Most cases (94%) were diagnosed with invasive tumors.

Genotypes of the individual htSNPs, including the nonsynonymous COMT Val158Met (rs4680), were not significantly associated with risk (Table 1). Associations between breast cancer and individual htSNPs did not vary by hormonal factors, menopausal status, family history of breast cancer, and tumor characteristics (results not shown).

Figure 1 shows the pairwise LD across COMT and its flanking genes, TXNRD2 and ARVCF, among the control population. Haplotypes in block 1, which extended through TXNRD2 and included the well-studied Val158Met (rs4680), were not associated with breast cancer risk compared with the most common haplotype (Table 2 ; global score statistic P = 0.76). The overall association between haplotypes in block 2 [encompassing the 3' untranslated region (UTR) of COMT and extending through ARVCF] with breast cancer risk did not reach statistical significance (global P = 0.09). However, the TGAG haplotype was associated with 31% increase in risk (OR, 1.31; 95% CI, 1.07-1.60) compared with the wild-type haplotype (TGAA). This association did not significantly differ by hormonal factors, menopausal status, family history of breast cancer, and tumor characteristics (results not shown).


View this table:
[in this window]
[in a new window]
  		Table 2. Age- and center-adjusted ORs and 95% CIs for the association between inferred COMT haplotypes and breast cancer in a case-control study of Polish women (1,995 cases and 2,296 controls)

 
Examination of the haplotype associations using the four-LD block structure observed in the BPC3 population did not alter our conclusions (data not shown). BPC3 LD block 1 was tagged by rs5993875, rs4485648, and rs8137828 (global P = 0.71). BPC3 LD block 2 was tagged by one htSNP, rs7290221. The global P value for BPC3 LD block 3, tagged by rs3810595, rs2239393, and rs4680, was 0.85. BPC3 LD block 4 was identical to LD block 2 in Table 2.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found no evidence for an association between breast cancer risk and common genetic variation in a LD block in COMT, which extended through its 5' neighbor TXNRD2, and included the putatively functional variant COMT Val158Met (rs4680). The lack of association with COMT Ex4-12 (Val158Met) is consistent with a recent meta-analysis (5). However, a haplotype (TGAG) in the second LD block encompassing the 3' UTR of COMT and ARVCF was associated with elevated breast cancer risk. None of the individual htSNPs in this block were significantly related to risk, and a causative genetic variant(s) that could be attributed to the observed association for the TGAG haplotype is unknown. Thus, it is possible that the causal variant(s) is in LD with the studied htSNPs. Further analyses are needed to dissect this observation.

The actual functional significance of the TGAG haplotype is unknown; however, this haplotype encompasses the 3' UTR regions of both COMT and ARVCF. The 3' UTR is important because it contains binding sites for regulatory proteins that control the mRNA translation process (16). Therefore, it is conceivable that genetic variation in the 3' UTR of COMT may affect translation control of COMT and modify breast cancer risk. However, it is also possible that the involvement of ARVCF in protein-protein interactions at adherent junctions (17, 18) may be important to breast cancer etiology. The matter is further complicated because the exact borders of COMT and ARVCF genes are unclear. For instance, Bray et al. (6) found that a SNP attributed to ARVCF that is found 2,607 bp 3' of STP (rs165599), which is located ~1,000 bp from ARVCF 1,727 bp 3' of STP assayed in our study (rs165728), is actually part of the COMT-MB cDNA transcript found in the brain.

Other studies have also found that haplotypes that encompass the 3' UTR of COMT are related to disease risk. In one study, a putatively functional three-SNP haplotype (COMT IVS1+255–COMT Ex4-12–ARVCF 2,607 bp 3' of STP) was found to be associated with an increased risk of breast cancer (19), which further suggests that genetic variants in the region around COMT 3' UTR may be important to breast cancer risk. It is notable that this region has also been associated with outcomes in schizophrenia and other mental disorders. For instance, haplotypes tagged by ARVCF 2,607 bp 3' of STP are related to increase risk for mental health outcomes (6, 7). Identification of genetic variation in similar regions of COMT in two different breast cancer studies, as well as in studies of other diseases, suggests that genetic variation in this region could be functionally important.

Our study had adequate power to detect modest associations between breast cancer risk and common variants. However, the power was more limited for associations that examined rare homozygous variant genotypes or for subgroup analyses. Our study has some of the highest participation rates attained in molecular epidemiologic studies with the collection of DNA (20), although we cannot exclude the possibility of selection bias. However, this potential bias is not expected to substantially affect our results, because carrier status is unlikely to be associated with reasons for nonparticipation. In addition, the frequency of alleles (Table 1), as well as the ORs of most of the well-defined breast cancer risk factors (8), was consistent with previous studies in European Americans. Population stratification is of minimal concern because our study population consisted of Polish women who are ethnically homogenous. Survival bias is unlikely to be relevant in our study because few cases died before interview (<0.5%) and the median time from diagnosis to blood collection was <2 months. In addition, the associations between SNPs and breast cancer risk did not vary by tumor size or nodal status (data not shown), indicating that survival bias, if present, is unlikely to alter our conclusions.

To our knowledge, this is the first study to comprehensively assess common genetic variation in COMT in relation to breast cancer risk. Our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3' UTR of COMT needs to be confirmed in independent study populations.


   Acknowledgments
 
Financial support: Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Neonila Szeszenia-Dabrowska (Nofer Institute of Occupational Medicine, Lodz, Poland) and Witold Zatonski (M. Sklodowska-Curie Institute of Oncology and Cancer Center, Warsaw, Poland) for their contribution to the Polish Breast Cancer Study; Anita Soni (Westat, Rockville, MD) and Pei Chao (IMS, Silver Spring, MD) for help in the management of the study; and the physicians, nurses, interviewers, and study participants for their dedicated efforts without which this work would not be possible.


   Footnotes
 
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

5 http://www.ncbi.nlm.nih.gov/projects/SNP/. Back

6 http://www-rcf.usc.edu/~stram/. Back

7 http://snp500cancer.nci.nih.gov. Back

8 http://www.broad.mit.edu/mpg/haploview/. Back

Received 4/10/06. Revised 8/ 1/06. Accepted 8/ 8/06.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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