Mutagenesis, Vol. 17, No. 2, 119-126,
March 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
The CYP17 MspA1 polymorphism and breast cancer risk: a meta-analysis
Bioinformatics Group, Centre for Molecular Genetics and Toxicology, School of Biological Sciences, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
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Abstract |
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Inter-individual differences in susceptibility to breast cancer are partially mediated through the levels of endogenous and exogenous steroid hormones. The CYP17 gene encodes P450c17
, an enzyme that is involved in the metabolism of steroid hormones. Increased endogenous steroid hormone levels have been associated with a MspA1 polymorphism in the 5'-promoter region of the CYP17 gene. The CYP17 MspA1 polymorphism has been postulated as being associated with the risk of developing breast cancer. However, the association between the CYP17 MspA1 polymorphism and breast cancer risk has been controversial in the literature. To re-examine this controversy, we have undertaken a meta-analysis of 15 case–control studies, which included a total of 4227 breast cancer cases and 4730 individual controls. The odds ratio (OR) was used to evaluate the risk of breast cancer for each study, using homozygosity of the wild-type allele as the control group. Statistical analysis showed no evidence of heterogeneity within the studies. The pooled ORs of breast cancer associated with the combined variant (A1/A2 + A2/A2) and the homozygous genotype (A2/A2) were 0.98 (95% CI 0.89–1.07) and 1.05 (95% CI 0.87–1.21), respectively. Similarly, the pooled ORs of advanced breast cancer associated with the combined variant and the homozygous genotype were 0.96 (95% CI 0.77–1.20) and 0.88 (95% CI 0.55–1.41), respectively. A pooling of the studies was also conducted for the various ethnic groups, but failed to show an association of CYP17 MspA1 polymorphism with breast cancer risk in the different ethnic groups. In addition, our results show that a possible protective effect for breast cancer risk of a later age at menarche was mainly limited to women with the A1 homozygous genotype. The OR for age at menarche (
13) was 0.87 (95% CI 0.62–1.17). Our results suggest that CYP17 MspA1 polymorphism may be at best a weak modifier of breast cancer risk but is not a significant independent risk factor. |
Introduction |
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In the UK breast cancer is the commonest cancer in women, accounting for ~25% of all female cancers. The incidence of breast cancer in the UK increased throughout the 1980s, reaching a peak in 1992. It has been estimated that one in ten UK women will develop breast cancer over their lifetime (Office for National Statistics, 1996
). The factors influencing the development of breast cancer risk in women probably result from complex interactions between many genetic and environmental factors, such as susceptibility genes, age at menarche, age at menopause, post-menopausal obesity, alcohol, the use of oestrogen replacement therapy, etc. (Dunning et al., 1999). The breast cancer susceptibility genes BRCA1 and BRCA2 play an important role in the familial disease, which is associated with a dominantly inherited increased risk of disease of at least 10- to 20-fold in female carriers (Ford et al., 1998). However, only 5–10% of all breast cancer cases can be explained by high penetrance germline mutations in genes such as BRCA1 and BRCA2 (Castilla et al., 1994). In the vast majority of cases there is little or no familial history of breast cancer and sporadic gene damage occurring during a woman's lifetime may play a more important role. However, other low penetrance susceptibility genes may exist which may alter individual predisposition to breast cancer.
CYP17 is one of the proposed low penetrance susceptibility genes which has received major attention because the gene codes for the enzyme cytochrome P450c17, which catalyzes both steroid 17-hydroxlyase and 17,20-lyase activities at key branch points in the oestrogen (oestradiol) biosynthesis pathway (Picado-Leonard and Miller, 1987; Dunning et al., 1999). 17-Hydroxylase activity converts steroids to precursors of the glucocorticoid cortisol and 17,20-lyase activity yields precursors of oestradiol and testosterone (Picado-Leonard and Miller, 1987). It is conceivable that changes in the expression levels or activities of the cytochrome P450c17 enzyme may have an impact on oestrogen biosynthesis. Recent studies have shown that oestrogen metabolites can bind to DNA and trigger damage (Cavalieri et al., 1997; Zhu and Conney, 1998). It has been suggested that oestrogen might be a complete carcinogen capable of causing genetic alterations and tumour initiation (Service, 1998). Since cytochrome P450c17 is important in oestrogen biosynthesis, increased or decreased activities of this enzyme may influence susceptibility to breast cancer.
The human CYP17 gene is located on chromosome 10 (10q24.3) (Fan et al., 1992). It contains eight exons and seven introns with a length of 6569 bp (Picado-Leonard and Miller, 1987). Inter-individual differences in susceptibility to breast cancer are partially mediated through the levels of endogenous and exogenous steroid hormones (Feigelson et al., 1996). To date, three polymorphisms have been described in the human CYP17 gene: a C
A transversion at nt 5471 in intron 6 (Crocitto et al., 1997); a GA transition at nt 47 in the 5'-untranslated region (UTR) promoter, which was detected by the loss of a NaeI restriction site (Miyoshi et al., 2000); a thymidine substituted for cytosine giving rise to a MspAI restriction site at nt 27 in the 5'-UTR promoter (Carey et al., 1994). Thus far, most of the published studies have examined the relationship between the MspAI polymorphism and breast cancer risk.
It has been suggested that the MspA1 polymorphism may confer susceptibility to breast cancer (Bergman-Jungestrom et al., 1999), since this polymorphism creates an additional Sp-1 type (CCACC box) promoter site 34 bp upstream from the initiation of translation but downstream from the transcription start site. This additional promoter site may increase the rate of transcription of the CYP17 gene and thus increase enzyme activity (Kadonaga et al., 1986). However, a study by Kristensen et al. (1999) suggested that there was no binding of human Sp-1 recombinant protein in vitro to a 20mer sequence containing the polymorphic site of the CYP17 allele. Hence, there was no interaction between Sp-1 and the polymorphic CYP17 5'-UTR sequence. The MspAI polymorphism gives rise to three different genotypes: a homozygous wild-type (A1/A1), a heterozygous variant (A1/A2) and a homozygous variant (A2/A2). The A2 allele has been associated with increased breast cancer susceptibility (Feigelson et al., 1997; Bergman-Jungestrom et al., 1999), but conflicting results have been obtained in some studies (Dunning et al., 1998; Haiman et al., 1999; Mitrunen et al., 2000). Over the past few years, the influence of the CYP17 MspA1 polymorphism had been reviewed in several studies (Coughlin and Piper, 1999; Dunning et al., 1999; Kristensen and Børresen-Dale, 2000; Thompson and Ambrosone, 2000; Weber and Nathanson, 2000). Our study focuses on a meta-analysis of all the available published case–control studies from January 1994 to June 2001 in order to assess the extent of possible association between the CYP17 MspA1 polymorphism and susceptibility to breast cancer.
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Materials and methods |
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Selection of studies
A MEDLINE search of the literature was conducted to identify studies with information on CYP17 polymorphisms and breast cancer risk over the period from January 1994 to June 2001, using the search terms `CYP17', `breast neoplasms' and `polymorphisms'. The citations in the identified articles and reviews were also manually searched to find additional studies. Only case–control studies of the CYP17 polymorphism in association with female breast cancer susceptibility which did not contain overlapping data were eligible for inclusion. A total of 14 articles were identified and included, which detail 15 case–control studies analysing the relationship between the CYP17 polymorphism and breast cancer risk. Additionally, the methodology for analysing the CYP17 polymorphism was standardized (Blomeke and Shields, 1999
). The polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) method was employed in 13 case–control studies and the polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) method was employed in one study (Miyoshi et al., 2000). In order to compare the design of the case–control studies, the data were analysed using the following categories: the number of cancer cases and controls, the variants in the cancer cases and controls, the relevant pathology and the covariates examined. Relevant information on the design of the case–control studies is included in Table I.
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Statistical analysis
The odds ratios (ORs) of the combined variant and homozygous genotypes of the CYP17 gene were calculated for each study on the basis of the raw data provided and their corresponding 95% confidence intervals were estimated by the method of Woolf (Woolf, 1955
; Breslow and Day, 1980). The combined variant was defined as the combination of both the heterozygous variant (A1/A2) and the homozygous variant (A2/A2), whereas homozygous genotype refers to the homozygous variant (A2/A2) alone. The 
2 test was used to investigate whether the genotype frequencies in controls were consistent with the Hardy–Weinberg equilibrium. Each study was treated as a separate stratum, with the homozygous wild-type used as the control group for each study. To take into account the possibility of heterogeneity across the studies, a statistical test for heterogeneity across studies was performed using the `large sample test' based on the Q statistic (DerSimonian and Laird, 1986). Meta-analysis was conducted by the Mantel–Haenszel method, which is based upon estimating a summary OR from a series of case–control studies (Mantel and Haenszel, 1959). The summary ORs were assessed by calculating a weighted average of ORs for all of the studies. The analyses were also conducted on subgroups of studies based on other features (ethnic group, age at menarche and menopausal status). The power of the study was estimated as the probability of finding a significant association between the CYP17 polymorphism and breast cancer risk at the 0.05 significance level, assuming that the OR is 1.5 or 2, and was estimated on the basis of the method published by Schlesselman et al. (1982). |
Results |
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Study design
Fourteen articles detailing 15 case–control studies investigating a possible association between the CYP17 MspA1 polymorphism and breast cancer risk were identified from the published literature and were suitable for analysis. These are shown in detail in Table I
. The study of Feigelson et al. (1997) was not included in the analyses because the same data were available in a later publication by the same group (Feigelson et al., 2001). Data on familial diseases were not considered for the pooling analysis (Helzlsouer et al., 1998; Spurdle et al., 2000) and data on mono- or bilateral breast cancer were pooled together for analysis (Kuligina et al., 2000). The study of Young et al. (1999) contained data on both male and female breast cancer, however, only data from this paper on female breast cancer were included for our analyses. Weston et al. (1998) reported the frequencies of the CYP17 genotype in cancer cases and individual controls in three ethnic groups, i.e. Caucasians, African-Americans and Hispanics. These were treated as three case–control studies for our analyses. However, the case–control study of the Hispanic group was excluded from our analysis because the control individuals showed a departure of genotype frequencies from the Hardy–Weinberg equilibrium.
Of the 15 case–control studies selected for meta-analysis, six studies were conducted in European countries and five in the USA. The sizes of the case–control studies reported varied substantially (ranging from 97 to 2126 individuals). Eleven studies were pathologically confirmed. The frequencies of CYP17 MspA1 homozygous alleles ranged from 5.7 to 35.8% in the cancer cases and the individual controls. In the control series, hospital-based controls were used in three studies (Table I). Controls were age matched to cases in a proportion of the studies, but this was not universal. In a number of the studies the association between CYP17 MspA1 polymorphism and breast cancer risk was analysed in a stratified manner or by logistic regression, taking into account other covariates (such as age, menopausal status, etc.), which are detailed in Table I. The studies in our analysis included a total of 4227 breast cancer cases and 4730 individual controls.
Table I shows the power of the individual studies to assess an association between the CYP17 polymorphism and breast cancer risk if the relative risk (RR) is 1.5 or 2. A statistical power >80% was obtained in seven of the 14 studies if the OR was 2.0 ( = 0.05, two-tailed test). However, if the OR was 1.5, only four of the 14 studies had a statistical power to demonstrate an association >80%.
Meta-analysis
The results of the pooled analysis and the individual studies of the CYP17 MspA1 polymorphism and the risks of developing breast cancer calculated for the 15 case–control studies are presented in Table II. The OR for an association of CYP17 MspA1 homozygosity and breast cancer risk varied substantially (ranging from 0.62 to 3.21). The value of the median OR was greater than unity in six of the studies. As expected, studies with small sample sizes produced a wide range of results and a narrower range of results can be seen for the studies with larger sample sizes (Figure 1). A plot of CYP17 MspA1 homozygosity and breast cancer risk showed a trend towards a less significant association in the larger studies (Figure 1). Tests for heterogeneity across the studies were performed before the studies were pooled for analysis (Q = 13.21, 14 df, P = 0.5). These provided no evidence for heterogeneity between the individual studies related to CYP17 MspA1 homozygosity. The plot of the ORs (95% confidence intervals, CI) for the CYP17 MspA1 homozygous genotype and breast cancer risk is shown in Figure 1. The overall OR (Mantel–Haenszel estimate) was 1.05 (95% CI 0.87–1.21). Similarly, tests for heterogeneity between the studies related to the CYP17 MspA1 combined variant also showed no significant heterogeneity (Q = 14.50, 14 df, P = 0.4). The overall OR associated with the CYP17 MspA1 combined variant was 0.98 (95% CI 0.89–1.07) (Figure 2).
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To determine the effect of the CYP17 MspA1 polymorphism on the risk of developing specific histological types of breast cancer, we examined advanced breast cancer based on the data derived from any relevant study which included histological information. Advanced breast cancer was defined as the patient having regional metastatic disease in more than one lymph node. Tests for heterogeneity between the studies showed no evidence of heterogeneity related to combined variant (Q = 2.90, 6 df, P = 0.9) and homozygosity (Q = 1.75, 2 df, P > 0.3). Table II
shows the ORs of the combined variant and homozygosity with advanced breast cancer risk. The overall ORs for the combined variant and homozygosity were 0.96 (95% CI 0.77–1.20) and 0.88 (95% CI 0.55–1.41), respectively.
All of these analyses are based on the pooling of data from different ethnic groups. However, one potential bias in the case–control studies of the CYP17 MspA1 polymorphism and breast cancer risk may be an imbalance of ethnic groups among cases and controls. Different ethnic groups were shown to have different frequencies of the CYP17 MspA1 polymorphism in relation to breast cancer susceptibility (Table I). The frequencies of CYP17 MspA1 homozygosity were 15.4 and 21.2% in the Caucasian and Asian control populations, respectively (data shown in Table I). Of the data analysed, nine case–control studies were limited to Caucasians and three were on Asians. This ethnic specificity may be an important factor to take into account in analysing an association between CYP17 polymorphism and breast cancer susceptibility. The results for the CYP17 MspA1 polymorphism and breast cancer risk stratified by ethnic groups are shown in Table II. The ORs for breast cancer and the combined variant and homozygosity in the Caucasian population were 1.01 (95% CI 0.89–1.14; test for heterogeneity, Q = 11.27, 8 df, P = 0.2) and 1.04 (95% CI 0.86–1.26; test for heterogeneity, Q = 10.51, 8 df, P = 0.4), respectively, and in Asians, 0.86 (95% CI 0.65–1.15; test for heterogeneity, Q = 1.34, 2 df, P = 0.5) and 1.02 (95% CI 0.71–1.47; test for heterogeneity, Q = 1.25, 2 df, P = 0.5), respectively. When these studies were considered as a group, the risk for developing breast cancer associated with the combined variant and homozygosity were 0.98 (95% CI 0.87–1.10; test for heterogeneity, Q = 13.36, 11 df, P = 0.26) and 1.04 (95% CI 0.88–1.23; test for heterogeneity, Q = 11.9331, 11 df, P = 0.4), respectively.
Other risk factors, such as age at menarche and first full-term pregnancy or parity, menopausal status, body mass index (BMI), oophorectomy, hormone exposure, alcohol intake and smoking, may mediate breast cancer risk through their influence on endogenous hormone levels. Because of the possible influence of CYP17 MspA1 polymorphism on oestrogen biosynthesis, we assessed modification of hormone-related risk factors of breast cancer on the CYP17 MspA1 genotype, such as age at menarche and menopausal status. Other possible risk factors were not evaluated because the formatted data in some studies were not suitable for pooling analysis. The results for the modification analyses based on age at menarche and menopausal status are shown in Table II. Three studies have cancer cases and individual control data for the age at menarche suitable for investigating this potential association (Helzlsouer et al., 1998; Haiman et al., 1999; Mitrunen et al., 2000). The ORs for age at menarche (13) were 0.87 (95% CI 0.65–1.17; test for heterogeneity, Q = 4.62, 2 df, P = 0.1) among women with the A1 homozygosity and 0.93 (95% CI 0.74–1.17; test for heterogeneity, Q = 2.31, 2 df, P = 0.5) among women with the combined variant. Similarly, four studies have cancer cases and individual control data on menopausal status which allowed analysis of this potential association (Helzlsouer et al., 1998; Haiman et al., 1999; Huang et al., 1999; Mitrunen et al., 2000). The ORs for pre-menopausal women with the combined variant and homozyosity were 0.79 (95% CI 0.57–1.09; test for heterogeneity, Q = 1.62, 2 df, P = 0.48) and 0.79 (95% CI 0.58–1.08; test for heterogeneity, Q = 1.62, 2 df, P = 0.48), respectively. The ORs for post-menopausal women with the combined variant and homozygosity were 0.99 (95% CI 0.71–1.38; test for heterogeneity, Q = 0,17, 3 df, P = 0.9) and 1.14 (95% CI 0.75–1.74; test for heterogeneity, Q = 0.36, 2 df, P = 0.85), respectively.
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Discussion |
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Carey et al. (1994) first identified the MspA1 polymorphism of the CYP17 gene and revealed a significant association with polycystic ovaries and male pattern baldness. They hypothesized that the number of recognition sites for the constitutive transcription factor Sp-1 may correlate with promoter activity and further up-regulate transcription of the CYP17 gene, which might in turn affect oestrogen biosynthesis. However, this hypothesis could not be verified experimentally in vitro by Kristensen et al. (1999), who suggested that the MspA1 polymorphism in the 5'-flanking region of the CYP17 gene does not influence binding to Sp-1 sites. Neither do the results of our meta-analysis support this hypothesis. The results show that the CYP17 MspA1 polymorphism is not associated with either increased breast cancer risk or with advanced breast cancer risk.
In our overview of all the studies it was clear that the design of some case–control studies in evaluating the CYP17 MspA1 polymorphism as a risk factor for breast cancer was less than optimal. Some of the case–control studies analysed were based on a comparison of cancer cases and hospital-based controls. The use of healthy controls would be more appropriate because controls with non-malignant disease might influence the frequencies of the CYP17 MspA1 genotype in determining susceptibility to cancer. In order to clarify the interplay between genotype and cancer risk an adequate sample size is one of the crucial factors in the design of case–control studies. In some of the studies failure to demonstrate a relationship may be partly due to a lack of statistical power. If the CYP17 MspA1 A2 allele is associated with a 1.5-fold increased risk of breast cancer, most of the published case–control studies lacked the power to demonstrate such a moderate effect.
In this meta-analysis only tabular data from the published studies were used to calculate the crude OR. Ideally, ORs should be evaluated by adjustment for breast cancer risk factors such as age at menarche, ethnicity, menopause, BMI, etc. This was not performed in our analysis because some of studies did not contain data suitable for calculating ORs and the variance studies often adjusted different factors when determining the risk of developing breast cancer. Although adjustment for related risk factors can modify OR estimates, this would not meaningfully change the ORs of interest here (Haiman et al., 1999; Huang et al., 1999). In addition, publication bias, which can occur when studies with null or unexpected results are not published, is of concern. We cannot exclude this probability from our meta-analysis and such situations could lead to incorrect conclusions.
It is now widely accepted that differences in ethnic distributions between case and control groups in population studies may be a source of potential bias, which might confound the results of a pooling analysis (Garte, 1998), since the association between cancer and a particular polymorphic site in one population might be of limited value as a biomarker for cancer in another population. Our results show that CYP17 MspA1 homozyosity is more frequent in the Asian population than in the Caucasian population. In our meta-analyses ethnic specificity was fully considered for an association between the CYP17 MspA1 polymorphism and breast cancer risk. However, the results obtained suggest that the value of overall ORs in the Asian population is nearly the same as that in the Caucasian population and there were no distinct differences in the ORs obtained from all the pooled studies. Hence, the frequencies of the CYP17 MspA1 genotype in different ethnic groups may not be a major factor in determining the risk of developing breast cancer.
Feigelson,H.S., Shanes,L.S., Pike,M.C., Coetzee,G.A., Stanczyk,F.Z. and Henderson,B.E. (1998) suggested that the combined variant was associated with elevated serum oestrogen and progesterone levels in the pre-menopausal period. This might influence the development of breast cancer because an increased level of serum oestrogen is one marker of breast cancer risk. It also implies that the combined variant might influence the age of onset of breast cancer. This hypothesis has been suggested by a study by Bergman-Jungestrom et al. (1999), whose results revealed that A2 allele carriers had a significantly increased risk for breast cancer in young women (OR = 2.0, 95% CI 1.1–3.5, P = 0.027). Over a woman's lifetime age is relevant in determining probable exposure to hormone-related risk factors. Age distribution should be fully considered in designing any case–control study to further evaluate an association between the CYP17 MspA1 genotype and breast cancer risk. However, age-matched cases and controls were only used in four studies (Helzlsouer et al., 1998; Weston et al., 1998; Haiman et al., 1999; Spurdle et al., 2000). Differences in age between cases and controls is a potential source of bias that may impact on the results of our meta-analysis.
To the best of our knowledge we have included all the available case–control studies of the CYP17 MspA1 polymorphism related to breast cancer susceptibility prior to July 2001. It was noted that two studies which showed an association between the CYP17 MspA1 polymorphism and familial disease were based on small sample sizes (Helzlsouer et al., 1998; Spurdle et al., 2000). Because of the limited information, we were unable to effectively assess the influence of the CYP17 MspA1 genotype on the risk of familial disease. Hence, more studies will be required to clarify the relationship between the CYP17 MspA1 polymorphism and familial disease.
Epidemiological studies have shown that breast cancer risk has been directly associated with exposure to endogenous or exogenous oestrogens (Feigelson and Henderson, 1996). Cumulative lifetime exposure to oestrogen, oestrogen metabolites and other physiological factors, as well as environmental exposures, could play an important role in the aetiology of breast cancer. An improved understanding of the interaction of xenobiotic exposures, endogenous physiology and genetic polymorphisms may help to identify women who are at an increased risk of developing breast cancer (Coughlin and Piper, 1999). We were unable to evaluate any gene–environment interaction other than age at menarche and menopausal status. Although such data were available for a small subset of studies, we were concerned that such limited data would not provide generalizable results. However, the study of gene–environment interactions may enhance our understanding of how some xenobiotic exposures influence breast cancer risk.
The pathway of oestrogen metabolism is mediated by the activities of multiple genes, such as CYP17, CYP1A1, catechol O-methyltransferase (COMT), 17ß-hydroxysteroid dehydrogenase 1 (HSD17B1) (Weber and Nathanson, 2000; Feigelson et al., 2001). The failure to demonstrate an association between the CYP17 MspA1 polymorphism and breast cancer risk may imply that variation of any single gene might have only a limited impact on oestrogen metabolism. It is conceivable that breast cancer risk related to any one locus will be small because gene–gene interactions are likely to operate. Therefore, the effect of the CYP17 MspA1 genotype on susceptibility to breast cancer could be minor, as is demonstrated here. A more comprehensive evaluation of an association between breast cancer risk and polymorphic variation will be needed to address this issue in a multigenic model. Two studies have attempted to elucidate this association and showed that the risk of breast cancer increased significantly as the number of putative high risk genotypes increased (Huang et al., 1999; Feigelson et al., 2001). These findings suggest that breast cancer has a strong genetic component. A multigenic model of breast cancer could contribute to our understanding of high risk alleles and, ultimately, prevent breast cancer.
The findings of our meta-analysis suggest that the CYP17 MspA1 genotype alone does not show an association with an increased risk of breast cancer, even when stratified by subgroup. This finding is perhaps not surprising, because the metabolic evidence to support the role of CYP17 MspA1 as a breast cancer risk factor is not strong. Although P450C17 is one of the key enzymes involved in oestrogen biosynthesis and mediates both steroid 17-hydroxylasa and 17,20-lyase activity (Dunning et al., 1999), the activity of human CYP17 is primarily expressed in ovarian theca cells and the adrenal cortex (Picado-Leonard and Miller, 1987) and, therefore, increased breast cancer risk directly associated with the CYP17 MspA1 genotype has to be mediated by blood-borne metabolites.
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Acknowledgments |
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We would like to thank the anonymous reviewers for their valuable comments. During the course of the study Z.Y. was supported by a graduate studentship provided by Phillip Morris Products SA.
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Notes |
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1 To whom correspondence should be addressed. Tel: +44 1792 205678; Fax: +44 1792 295447; Email: bazheye{at}swansea.ac.uk
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References |
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Received on March 28, 2001; accepted on October 10, 2001.
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