Meta- and Pooled Analyses of the Cytochrome P-450 1B1 Val432Leu Polymorphism and Breast Cancer: A HuGE–GSEC Review

¹ Scientific Direction, Ospedale Maggiore, Milan, Italy
² Department of Preventive Medicine, Faculty of Medicine, Institute of Community Medicine, University of Tromsø, Tromsø, Norway
³ Department of Preventive Medicine, Seoul National University, College of Medicine, Institute of Environmental Medicine, Seoul, South Korea
⁴ Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
⁵ Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway
⁶ Department of Gastrointestinal Medical Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, TX
⁷ Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
⁸ Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
⁹ Center of Occupational Diseases, National Institute of Public Health, Prague, Czech Republic
¹⁰ Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN
¹¹ Department of Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
¹² University of Pittsburgh Cancer Institute, Pittsburgh, PA

Correspondence to Dr. Emanuela Taioli, University of Pittsburgh Cancer Institute, 5150 Center Avenue, Pittsburgh, PA 15232 (e-mail: taiolien@upmc.edu ).

Received for publication April 14, 2006. Accepted for publication May 26, 2006.

The association between the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer was assessed through a meta-analysis of all published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database (http://www.upci.upmc.edu/research/ccps/ccontrol/g_intro.html). GSEC is a collaborative project that gathers information on studies of metabolic gene polymorphisms and cancer. Thirteen articles were included in the meta-analysis (14,331 subjects; 7,514 cases, 6,817 controls); nine data sets were included in the pooled analysis (6,842 subjects; 3,391 cases, 3,451 controls). A summary meta- or pooled estimate of the association between the CYP1B1 Val432Leu polymorphism and breast cancer could not be calculated because of statistically significant heterogeneity in the point estimates among studies. No association between the CYP1B1 Val432Leu polymorphism and breast cancer was observed in Asians (for Val/Val and Val/Leu combined, odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.8, 1.2). An inverse association was observed in populations of mixed/African origin (OR = 0.8, 95% CI: 0.7, 0.9). The pooled analysis suggested a possible association in Caucasians (for Val/Val and Val/Leu combined, OR = 1.5, 95% CI: 1.1, 2.1), with effect modification across age categories. The observed effect of age on the association in Caucasians indicates that further studies are needed on the role of CYP1B1 Val432Leu in estrogen metabolism according to age, ethnicity, and menopausal status.

Keywords: breast neoplasms; CYP1B1; cytochrome P-450 enzyme system; genetics; hormones; meta-analysis; polymorphism, genetic; review [publication type]
Abbreviations: CI, confidence interval; CYP, cytochrome P-450; GSEC, Genetic Susceptibility to Environmental Carcinogens; OR, odds ratio

Gene
The cytochrome P-450 1B1 (CYP1B1) gene maps to chromosome 2p22–p21 (1) and contains three exons and two introns (2). The entire coding sequence of the gene is contained in exons 2 and 3. The gene is expressed in monocytes and macrophages, as shown by the measurement of both mRNA and proteins (3, 4), and in several other extrahepatic tissues and organs, such as the kidney, prostate, breast, uterus, ovary, and placenta (5–9).

CYP1B1 is an inducible enzyme regulated through the aryl hydrocarbon receptor (10) and is activated through this receptor by polycyclic aromatic hydrocarbons and dioxin-like compounds (11). It is capable of activating a variety of carcinogens, such as arylamines, and is involved in the metabolism of estradiol, like several genes of the cytochrome P-450 (CYP) family; CYP1B1 encodes for an enzyme that catalyzes the formation of both 2- and 4-hydroxyestrone, with higher activity on the 4- compound (12, 13).

Levels of CYP1B1 gene expression in white blood cells have been investigated according to gender; results showed that females have higher expression than males (14), although these data were not confirmed in other studies (15, 16). CYP1B1 gene expression during pregnancy has also been examined; it was found to be up-regulated in one study (17) but not in another (18).

Gene variants
There are several variants of CYP1B1 (http://www.cypalleles.ki.se/). There is a common C→G transversion at position 1666 in exon 3, resulting in an amino acid substitution of leucine (Leu) with valine (Val) at codon 432 (13, 19). Exon 3 encodes the heme-binding domain, a region that is critical to the catalytic function of the gene (19). Several other polymorphisms in the CYP1B1 gene have been described as well (http://www.cypalleles.ki.se/); four of them result in amino acid substitutions (20). They are: Arg→Gly at codon 48, Ala→Ser at codon 119, Leu→Val at codon 432, and Asn→Ser at codon 453.

Population frequency
The valine substitution is reported to be present at an allele frequency of 0.43 in Caucasians, while in African Americans the allele frequency is 0.75 (21) and in Asians it is 0.23 (22).

We calculated the pooled frequencies of the CYP1B1 Val432Leu polymorphism from published studies on healthy subjects. A MEDLINE search of articles published through August 2005 produced 29 papers, with a total of 10,252 subjects belonging to different ethnic groups. The frequency of the Leu/Leu genotype is 0.70 (95 percent confidence interval (CI): 0.69, 0.72) in Asians and 0.31 (95 percent CI: 0.30, 0.32) in Caucasians, while it is lower in African-Americans: 0.08 (95 percent CI: 0.05, 0.11) (Table 1).

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Table 1: Frequencies of the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism in healthy populations included in a meta-analysis

Selection criteria
We assessed the association between the CYP1B1 Val432Leu polymorphism and breast cancer through a meta-analysis of all published papers and a pooled analysis of both published and unpublished studies. We searched MEDLINE and EMBASE up to September 2005, using different combinations of the keywords "cytochrome P-450 1B1," "CYP1B1," and "breast," without any restriction on language. We supplemented the computer search by consulting bibliographies from the articles found through the MEDLINE search and by looking at a review paper (40).

An initial screening of all abstracts produced 22 articles containing information on both CYP1B1 Val432Leu polymorphisms and breast cancer. Eligible studies were case-control, genotype-based studies that reported the frequency of the CYP1B1 Val432Leu polymorphism or the odds ratio for the relation between CYP1B1 Val432Leu and breast cancer. Both hospital-based and population-based case-control studies were included in the analysis. Of the selected papers, four were excluded because they were case-only studies, one was excluded because it was a family-based study, one was excluded because it reported data only on CYP1B1 Val432Leu gene expression, and one was excluded because it was a review of published data (41). The subjects included in the paper by Kocabas et al. (42) completely overlapped with those in a previous article (43); therefore, only the study that included detailed analyses of the CYP1B1 Val432Leu polymorphism (42) was included. The subjects in the papers by Li et al. (44) and Zhu et al. (45) partially overlapped; therefore, we included the study with the largest numbers of cases and controls (45). The final number of articles considered for the present meta-analysis was 13, comprising a total of 14,331 subjects (7,514 cases and 6,817 controls). A description of these studies is given in Table 2.

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Table 2: Characteristics of case-control studies included in a meta-analysis of the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer

Data collection
The pooled analysis was performed using the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. The International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (http://www.upci.upmc.edu/research/ccps/ccontrol/g_intro.html) is a collaborative project that gathers information from both published and unpublished case-control studies on metabolic gene polymorphisms and cancer. The design of this study is explained in detail elsewhere (50). A questionnaire was provided to each investigator at the time of enrollment in the study, collecting information on the study design, the selection and source of controls, the laboratory methods used for genotyping, the source of DNA for genotype analysis, and the response rates for both cases and controls. Some of this information has been previously published (51). Studies that had information on CYP1B1 Val432Leu and breast cancer were selected from the GSEC database. The investigators of the published studies for which data were not available through the GSEC project were then contacted and asked to provide their data for this specific pooled analysis.

Of the 13 studies included in the meta-analysis, we were able to obtain data from seven (see Table 2 for details). The GSEC database contained two additional studies with unpublished data on the CYP1B1 Val432Leu polymorphism and breast cancer; therefore, the final number of data sets included in the pooled analysis was nine, with a total of 6,842 subjects (3,391 cases and 3,451 controls).

Statistical analysis
For the meta-analysis, the reported frequencies of CYP1B1 Val/Leu and Val/Val in cases and controls were extracted from the published studies, and the corresponding study-specific crude odds ratios and 95 percent confidence intervals for breast cancer risk were calculated. The departure of CYP1B1 Val432Leu frequencies from expectation under Hardy-Weinberg equilibrium was tested (52). Egger's test for assessment of publication bias (53) was performed on the overall data set and according to ethnicity (Caucasian, Asian, or other) and source of controls (healthy controls or hospitalized controls). Funnel plots were used for a graphical representation of publication bias.

The Q statistic was used to test the hypothesis of homogeneity among all of the studies and according to ethnicity and type of controls, with p values less than 0.05 indicating the presence of heterogeneity among studies. A fixed-effects model was used when the test for heterogeneity was not statistically significant, while a random-effects model was employed when heterogeneity across studies was statistically observed (54).

Summary odds ratios were calculated for all of the studies combined. Since two of the most important causes of heterogeneity among studies were ethnicity and source of controls, we calculated separate odds ratios to assess the association between breast cancer and the CYP1B1 Val432Leu polymorphism in subgroups of studies performed in different ethnic groups (Caucasians, Asians, others) and in subgroups of studies including hospitalized or healthy controls.

Individual data on breast cancer and CYP1B1 Val432Leu were extracted from the GSEC data set and were used for the pooled analysis. We assessed associations between several variables and breast cancer risk by using general linear models for continuous variables and by calculating crude odds ratios for binary variables. Crude odds ratios for the association between the CYP1B1 Val432Leu polymorphism and breast cancer were calculated, and the chi-squared test for trend was performed. We then calculated adjusted odds ratios using multivariate logistic regression models. The pooled data were subsequently stratified according to ethnicity. The large number of subjects included in the pooled analysis allowed us to perform further stratified analyses according to age and histologic type.

Meta-analysis
The study-specific odds ratios and the meta-odds ratios for all of the studies are presented in Table 2. Figure 1 contains a graphical representation of the study-specific odds ratios. Bailey et al. (19) reported the results of separate analyses for two different ethnic groups (Caucasians and African Americans); therefore, this study was included both in the analysis of Caucasians (by calculating the odds ratios for Caucasians only) and in the analysis of persons of other ethnic groups (by calculating the odds ratios for African Americans only). Among the seven studies on Caucasians, three reported no association between the CYP1B1 Val432Leu polymorphism and breast cancer (19, 46, 48), while three reported that the valine allele had a risk effect (28, 42, 55); one study reported an inverse association between the valine allele and breast cancer (47). Statistical significance for the association between breast cancer and the CYP1B1 Val/Val polymorphism was reached in only one study (55) (odds ratio (OR) = 3.3, 95 percent CI: 1.8, 6.2).

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Figure 1: Study-specific and meta-analysis odds ratios for the relation between cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphisms (Val/Leu + Val/Val) and breast cancer, according to ethnicity. Bars, 95% confidence interval.

Among the other studies conducted in African Americans (19) or in mixed populations (45, 56, 57), two (19, 56) presented odds ratios spread around the null effect, while two (45, 57) reported an inverse association between the Val/Val genotype and breast cancer (OR = 0.4 (95 percent CI: 0.1, 1.0) and OR = 0.7 (95 percent CI: 0.6, 0.9), respectively) and for the Val/Val and Val/Leu genotypes combined (OR = 0.4 (95 percent CI: 0.1, 1.0) and OR = 0.8 (95 percent CI: 0.7, 0.9), respectively).

The overall meta-odds ratio for the combination of the CYP1B1 Val/Val and Val/Leu genotypes was null; it is not reported because of the large heterogeneity (Q test: p < 0.001), although there was no evidence of publication bias (Egger's test: p = 0.26). When a stratified analysis according to ethnicity was performed, no association was observed between the CYP1B1 Val432Leu polymorphism and breast cancer among Asians (for the Val/Val and Val/Leu genotypes combined, OR = 1.0, 95 percent CI: 0.8, 1.2), while a significant inverse association between the valine allele and breast cancer was observed for the four studies including African Americans or mixed populations (for the Val/Val and Val/Leu genotypes combined, OR = 0.8, 95 percent CI: 0.7, 0.9). The result of the test for heterogeneity was strongly statistically significant for the Caucasian studies (Q test: p < 0.001); therefore, a combined estimate was not calculated for this ethnic group. Among the 13 studies, nine included healthy controls and four included hospitalized controls; the odds ratios were similar in the two groups of studies, but with statistically significant heterogeneity.

Data on the relation between breast cancer and three other CYP1B1 polymorphisms (Asn453Ser, Ala119Ser, and Arg48Gly) were reported in the studies selected for the CYP1B1 Val432Leu meta-analysis. Of the four studies including information on Asn453Ser, none reported a significant association with breast cancer. Of the five studies on the Ala119Ser polymorphism, one (49) found a higher risk of breast cancer in subjects carrying at least one serine allele (OR = 1.57, 95 percent CI: 1.12, 2.20), while another study (48) reported an inverse association between the serine allele and breast cancer (for the Ala/Ser and Ser/Ser genotypes combined, OR = 0.32, 95 percent CI: 0.18, 0.60). The same study found an inverse association between the Arg48Gly polymorphism and breast cancer (for the Arg/Gly and Gly/Gly genotypes combined, OR = 0.13, 95 percent CI: 0.07, 0.23), while the other two studies found no association between the Arg48Gly polymorphism and breast cancer.

Pooled analysis
The pooled analysis included nine studies, for a total of 3,391 cases and 3,451 controls. Among the personal and reproductive variables for which data were available in the GSEC pooled analysis, family history of cancer, late age at first birth, late age at menopause, and low number of livebirths were found to be associated with breast cancer. No association was observed for active smoking, reported exposure to environmental tobacco smoke, or alcohol consumption (data not shown).

The crude and adjusted odds ratios for the association between the CYP1B1 Val432Leu polymorphism and breast cancer are presented in Table 3. An overall estimate was not calculated because of statistically significant heterogeneity, as previously observed in the meta-analysis. Crude odds ratios were found to be significantly higher than 1.00 in Caucasians for both the Val/Leu and Val/Val genotypes, with a significant trend, but after adjustment for study, age, and smoking, the association was only present for Val/Leu alone and the Val/Leu + Val/Val genotypes combined. No significant effect of the CYP1B1 Val432Leu polymorphism on breast cancer risk was observed in Asian or African-American subjects.

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Table 3: Association between the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer in a pooled analysis of studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) project

The availability of individual data allowed us to analyze the data according to age groups. A significant effect of age on the association between CYP1B1 Val432Leu and breast cancer was found in Caucasians, while the same effect was not observed in the other ethnic groups (Figures 2 and 3). For Caucasians, the risk of breast cancer increased between the ages of 45 years and 59 years, while it was lower among older and younger women.

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Figure 2: Association between cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphisms (Val/Leu + Val/Val) and breast cancer, according to age and ethnicity, in a pooled analysis of studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) project. The numbers of Asian, Caucasian, and African-American subjects with CYP1B1 Val432Leu polymorphisms in each age class were, respectively: <45 years: 316, 277, and 64; 45–50 years: 174, 186, and 24; 51–54 years: 67, 94, and 94; 55–59 years: 68, 226, and 257; ≥60 years: 78, 651, and 698.

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Figure 3: Association between cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphisms (Val/Leu + Val/Val) and breast cancer, according to age, among Caucasians in a pooled analysis of studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) project. Corresponding odds ratios (with 95% confidence intervals in parentheses) are presented near each data point. The numbers of subjects with CYP1B1 Val432Leu polymorphisms in each age class were: <45 years: 191 (Val/Leu) and 86 (Val/Val); 45–50 years: 123 (Val/Leu) and 63 (Val/Val); 51–54 years: 70 (Val/Leu) and 24 (Val/Val); 55–59 years: 154 (Val/Leu) and 72 (Val/Val); ≥60 years: 458 (Val/Leu) and 193 (Val/Val).

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Table 4: Association between the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer in a pooled analysis of studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) project, according to histologic type

This meta-analysis confirmed the lack of association between the CYP1B1 Val432Leu polymorphism and breast cancer risk among Caucasian and Asian subjects, as reported in a previous meta-analysis with smaller numbers (40). A significant inverse association between the valine allele and breast cancer risk was observed in the studies including African Americans or mixed populations.

The pooled analysis suggests a possible association of both the Val/Leu and Val/Val genotypes with breast cancer in Caucasians; however, no significant effect was observed in Asian or African-American subjects. To our knowledge, this was the first comprehensive pooled analysis assessing the role of the CYP1B1 Val432Leu polymorphism in breast cancer. Since the pooled data set included additional information on several cofactors, it was possible to adjust the point estimates for potentially confounding factors and to perform stratified analyses.

Among the genes involved in hormone production and metabolism, CYP1B1 has been shown to have an important role in estrogen metabolism, catalyzing principally the formation of 4-hydroxyestradiol, a carcinogenic metabolite that retains estrogenic activity (16). This enzyme also hydroxylates the estradiol in the C-2 position, although to a lower extent. CYP1B1 appears to be implicated in the metabolic activation of a number of environmental carcinogens, such as arylamines, heterocyclic amines, benzo(a)pyrene, and polycyclic aromatic hydrocarbons (11, 58). The change in amino acid from valine to leucine has been shown to increase the activity of the CYP1B1 enzyme on a variety of substrates, including procarcinogens and gonadal steroid hormones (12). The increased formation of 4-hydroxyestrone induced by the CYP1B1 enzyme could be a possible risk factor for breast cancer (56). We reported previously (59) that women with the leucine substitution had higher 2-/16- hydroxyestrone metabolites than women carrying the other CYP1B1 genotypes. Despite the premises, most of the individual studies included in the present analysis showed no association between the CYP1B1 Val432Leu polymorphism and breast cancer, and there was a large amount of heterogeneity. One possible explanation may be the relatively small sample size in some studies (40); another could be the observed differences in reported genotype frequencies across studies, as well as some differences in the original study designs. While most of the articles were case-control studies, the study by Dunning et al. (47) was a case-cohort study, and the studies by Le Marchand et al. (57) and De Vivo et al. (28) were case-control studies nested within a cohort. However, when these three studies were excluded from the meta-analysis, the test of heterogeneity still remained significant (results not shown). The studies included in the pooled analysis were all case-control studies by definition; therefore, the heterogeneity observed in the pooled analysis is unlikely to be explained by differences in study design.

Since breast cancer is a hormone-related disease, we considered age as a possible reason for heterogeneity. In fact, we observed that the three Caucasian studies responsible for the statistical heterogeneity in the meta-analysis (28, 42, 55) all included younger women; therefore, we hypothesized that age could modify the effect of CYP1B1 Val432Leu on cancer risk. We tested this hypothesis through the pooled analysis, where we found a significant effect of age on the association between CYP1B1 Val432Leu and breast cancer in Caucasians. The risk of breast cancer seemed to be higher for the central age classes (45–59 years), while it was lower in either older or younger women. Aside from chance, a possible explanation for this could involve the change in estrogen levels, and therefore in estrogen metabolism, that occurs around menopause. Changes in hormonal patterns, in conjunction with weight changes, could make polymorphisms in genes involved in estrogen metabolism key elements during the menopausal transition, while they could be less important in younger or older women. This hypothesis, deriving from the large number of subjects included in our pooled analysis, has never been put forward, but it needs to be tested in a large study of women of different age groups.

Potential public health impact
At the moment, the potential public health impact of these results is minimal, since there is not sufficient evidence for a role of the CYP1B1 Val432Leu polymorphism in breast cancer etiology. Therefore, population testing for the CYP1B1 Val432Leu polymorphism is not indicated.

Laboratory testing
The detailed methods used for determining the presence of the CYP1B1 Val432Leu polymorphism were described in each article. Most of the studies included in the present analyses used genomic DNA extracted from blood. Two studies utilized breast tissue (46, 55) in addition to blood; one study utilized only breast tissue (19). Most investigators reported the use of polymerase chain reaction, with different reaction conditions and control samples. Rylander-Rudqvist et al. (46) reported the use of two different techniques, multiplex fluorescent solid-phase minisequencing and dynamic allele-specific hybridization; Dunning et al. (47) used TaqMan assays (Applied Biosystems, Warrington, United Kingdom) and sequencing; De Vivo et al. (28) used automated DNA sequencing; Watanabe et al. (49) used single-strand conformation polymorphism analysis; and Listgarten et al. (55) reported the use of an external genomic service.

Conclusions and implications for research
Overall, a possible association between the CYP1B1 Val432Leu polymorphism and breast cancer could be detected in Caucasians, while a negative association was suggested in populations of mixed/African-American origin. Among Caucasians, a significant effect of age on the association was found in the pooled analysis. The risk of breast cancer seemed to be higher for the central age classes (45–59 years), while it decreased for older and younger women. Further studies are needed in order to investigate the effect of CYP1B1 Val432Leu on estrogen metabolism in different age groups and ethnic groups and in premenopausal women versus postmenopausal women.

This project was supported by grant OC B20.001 from the European Program for Co-Operation in Science and Technology (COST) (Action B20) and by the ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility) Network of Excellence (European Union Sixth Framework Programme for Research and Development).

Conflict of interest: none declared.

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