CYP1A1 gene polymorphisms and breast cancer risk: a HuGE review

HuGE Cancer Epidemiology

HuGE Study

Masson, L. Sharp, S.C. Cotton and J. Little. Cytochrome P-450 1A1 Gene Polymorphisms and Risk of Breast Cancer: A HuGE Review. Am. J. Epidemiol. (15 May 2005) 161 (10): 901-915.

Category of HuGE Information

The types of information available from the article:

Prevalence of gene variant

Gene-disease association

Gene-environment interaction

Gene-gene interaction

Cytochrome P-450 (CYP) 1A1 plays a key role in phase I metabolism of polycyclic aromatic hydrocarbons and in estrogen metabolism. It is expressed predominantly in extrahepatic tissues, including the breast. Four CYP1A1 gene polymorphisms (3801T-C, Ile462Val, 3205T-C, and Thr461Asp) have been studied in relation to breast cancer. The 3801C variant is more common than the Val variant. Both variants occur more frequently in Asians than in White populations. The 3205T-C polymorphism has been observed in African-Americans only. Little data are available on the geographic/ethnic distribution of the Thr461Asp polymorphism. The functional significance of the polymorphisms is unclear. In 17 studies, no consistent association between breast cancer and CYP1A1 genotype was found. Meta-analysis found no significant risk for the genotypes 1) 3801C/C (relative risk (RR) = 0.97, 95% confidence interval (CI): 0.52, 1.80) or 3801T/C (RR = 0.91, 95% CI: 0.70, 1.19) versus 3801T/T, 2) Val/Val (RR = 1.04, 95% CI: 0.63, 1.74) or Ile/Val (RR = 0.92, 95% CI: 0.76, 1.10) versus Ile/Ile, or 3) Asp/Asp (RR = 0.95, 95% CI: 0.20, 4.49) or Thr/Asp (RR = 1.12, 95% CI: 0.87, 1.43) versus Thr/Thr. Future studies should explore possible interactions between CYP1A1 and sources of polycyclic aromatic hydrocarbons, markers of estrogen exposure, other lifestyle factors influencing hormonal levels, and other genes involved in polycyclic aromatic hydrocarbon metabolism or hormonal biosynthesis.

Gene:

Gene Name, Chromosome location, and gene product/function:

Cytochrome P-450 (CYP) 1A1 is a key enzyme in phase I bioactivation of xenobiotics. It contributes to aryl hydrocarbon hydroxylase activity, catalyzing the first step in the metabolism of a number of polycyclic aromatic hydrocarbons (PAHs), such as the tobacco carcinogen benzo[a]pyrene, to their ultimate DNA-binding forms. It is also involved in estrogen metabolism, catalyzing the hydroxylation of 17?-estradiol at the C-2 position.

The CYP1A1 gene, located at 15q22-q24, comprises seven exons and six introns and spans 5,810 base pairs. In humans, CYP1A1 is under the regulatory control of the aryl hydrocarbon receptor, a transcription factor that regulates gene expression.

CYP1A1 expression occurs predominantly in extrahepatic tissue. CYP1A1 messenger RNA has been detected in normal and cancerous breast tissue and can be induced in human-breast-derived cell lines.

Alleles: CYP1 family:

CYP1A1; CYP1A2; CYP1B1; CYP2 family: CYP2A6; CYP2A13; CYP2B6; CYP2C8; CYP2C9; CYP2C19; CYP2D6; CYP2E1; CYP2F1; CYP2J2; CYP2R1; CYP2S1; CYP2W1

CYP3 family:

CYP3A4; CYP3A5; CYP3A7; CYP3A43

CYP4 family:

CYP4A11; CYP4A22; CYP4B1; CYP4F2

CYP>4 families:

CYP5A1

CYP8A1

CYP19A1

CYP21A2

CYP26A1

OMIM #: 108330

Environmental Factors:

1. PAHs (polyaromatic hydrocarbons)

2. Tobacco smoke

3. Estrogen

4. Fried foods

5. Alcohol

6. PCBs (polychlorinated biphenols)

Health Outcomes:

1. Incidence of breast cancer risk in association with C-P450 mutations

2. Determine variants of C-P450 polymorphisms in specific ethnic populations

3. Determine gene-gene and gene-environment interactions for CP450 alleles and breast cancer.

Study design

This is a descriptive, cross-sectional study.

Assessment of environmental factors:

Environmental factor: Smoking

Exposure assessment and definition: genotype-smoking interactions light smokers (

Number of participants with exposure data: unknown small number

Environmental factor: Polychlorinated biphenols

Exposure assessment and definition: plasma PCBs

Number of participants with exposure data:

Gene: Cytochrome P50 1A1

DNA source: Breast cancer tissue (tumor samples), blood samples

Methodology: Polymerase chain reaction

Analysis (see below)

Results

Study characteristics

Four studies took place in Japan, two in Taiwan, six in the United States, and one each in Canada, Brazil, France, Greece, and the United Kingdom. Thirteen studies analyzed the 3801T-C polymorphism (2,484 cases), 10 analyzed the Ile462Val polymorphism (3,535 cases), two analyzed the 3205T-C polymorphism (280 cases), and three analyzed the Thr461Asp polymorphism (2,245 cases).

In one study, case DNA was derived from tumor specimens; in the remainder, and for all control series, DNA came from blood samples. Of the U.S. studies, two involved subjects of whom the majority (or all) were White, three included more than one ethnic group (analyzed separately in two studies), and, in one, ethnicity was not reported. One study included postmenopausal women only; all others either consisted of both pre- and postmenopausal women (n = 6) or did not describe the subjects' menopausal status (n = 10). Eleven studies included fewer than 200 breast cancer cases.

In 15 studies, cases were recruited from clinics or hospital series; in one study, cases were identified from a cancer registry; and one study was nested within the Nurses' Health Study. Without information on all potentially eligible cases in the population, it is difficult to assess the generalizability of the results. At least four control series included "volunteers" from either an unspecified source or a convenient population such as medical workers -- a potential source of bias. Seven studies presented estimates adjusted for potential confounding factors.

In general, the studies considered the polymorphisms separately. Therefore, the effect of one polymorphism may have been overshadowed by the effects of others, whereas construction of haplotypes may have revealed effects that were not apparent by analyzing single polymorphisms. Studies of the Ile462Val polymorphism may have suffered from some minor misclassification due to the undetected presence of the Thr461Asp polymorphism.

3801T-C (CYP1A1*2A, CYP1A1*2B)

Most studies found no evidence of an association between the 3801T-C polymorphism and breast cancer risk. In Taiwan, women with the C/C genotype had a raised risk compared with other genotypes combined. African-American women with the C/C genotype also had an increased risk compared with those with the T/T genotype, but this study included only 25 cases. The 3801C variant was associated with reduced risk for Japanese and non-White Brazilian women. However, in both studies, the cases were surgical series, and controls were not population based.

Their meta-analysis included eight studies for which data were available for all three genotypes separately. Breast cancer risk did not differ from unity for C/C versus T/T (random-effects relative risk (RR) = 0.97, 95% CI: 0.52, 1.80; Q = 15.26, p = 0.08) or for T/C versus T/T (random-effects RR = 0.91, 95% CI: 0.70, 1.19; Q = 17.34, p = 0.07). The I2 statistics for these analyses were 41% and 42%, respectively, indicating moderate heterogeneity across studies.

Ile462Val (CYP1A1*2B, CYP1A1*2C)

A Japanese study found a significantly reduced risk for women with the Ile/Val genotype compared with the Ile/Ile genotype (RR = 0.66, 95% CI: 0.44, 0.99). However, meta-analysis found no association between breast cancer risk and the Val/Val (fixed-effects RR = 1.04, 95% CI: 0.63, 1.74; Q = 4.59, p = 0.33, I2 = 13%) or Ile/Val (fixed-effects RR = 0.92, 95% CI: 0.76, 1.10; Q = 11.57, p = 0.17, I2 = 31%) genotypes vs. The Ile/Ile genotype.

3205T-C (CYP1A1*3)

There was no association between the 3205C variant and breast cancer in the two available studies However, these studies each included small series (n = 27 and n = 59) of African-American breast cancer cases.

Thr461Asp (CYP1A1*4)

In a Canadian study, carriers of the Asp variant had an increased breast cancer risk (adjusted RR = 3.3, 95% CI: 1.1, 9.7). Results of the other studies, in White American women and African-American women, and in White women in England, were null. Meta-analysis found no association between disease risk and the Asp/Asp (fixed-effects RR = 0.95, 95% CI: 0.20, 4.49; Q = 0.52, p = 0.77, I2 = 0%) or Thr/Asp (fixed-effects RR = 1.12, 95% CI: 0.87, 1.43; Q = 0.89, p = 0.64, I2 = 0%) genotypes vs. The Thr/Thr genotype.

Combinations of genotypes

Taioli et al. assessed the impact of combinations of 3801T-C, Ile462Val, and 3205T-C genotypes on breast cancer risk. Compared with homozygotes for the 3801T, Ile, and 3205T alleles, only the 3801C/C genotype was associated with increased risk for African-American women (RR = 5.8, 95% CI: 1.0, 36.0), but the effect estimate was imprecise.

One study combined Ile462Val and Thr461Asp genotypes and found no significant effect in any of the three combined genotype groups relative to the group with the Ile/Ile and Thr/Thr genotypes. Another study assessed disease risk for subjects with either the Val or Asp variant; no significant association was found in White women or African-American women.

Subgroup analyses

Menopausal status, age at menarche, and estrogen and progesterone receptor status.

In a Taiwanese study, the association of the 3801C/C genotype with raised disease risk was evident in postmenopausal, but not premenopausal, women, and further analysis suggested that the relation might be more pronounced for women experiencing early menarche. Other studies found no association between the 3801C variant and breast cancer when subjects were stratified by menopausal status or age at menarche. There was no evidence for an association with the Ile462Val polymorphism for either pre- or postmenopausal women. In a Canadian study, the increased risk associated with the Thr461Asp polymorphism was evident for postmenopausal women only; however, a study in the United Kingdom found no difference in Thr461Asp genotypic risks by menopausal status. There were no significant associations between CYP1A1 polymorphisms and estrogen or progesterone receptor status.

Age at diagnosis and clinical characteristics.

Studies investigating CYP1A1 genotype and age at diagnosis of breast cancer have produced inconsistent results. The 3801C variant has been significantly associated with a higher frequency of lymph-node metastasis and the Val variant with a higher frequency of small tumors (

Survival

In a British study of 1,793 incident or prevalent breast cancer cases, the Ile462Val polymorphism was not related to survival (191). The hazard ratio was reduced for Thr/Asp heterozygotes compared with Thr/Thr homozygotes, but not significantly (hazard ratio = 0.67, 95% CI: 0.33, 1.37).

Interactions

If CYP1A1 is involved in breast cancer, it may influence disease risk by interacting with exposure (or indicators of exposure) to PAHs or estrogen, for example, or with other genes involved in the metabolism of carcinogens, estrogens, or other hormones. Sample size is particularly important in this context. For instance, to detect a multiplicative interaction, very large sample sizes are required for adequate power. Although the sample size needed to detect other types of interactions may be smaller, a priori it is not usually clear what model of interaction would be predicted.

Gene-environment interactions

Smoking.

In five studies investigating genotype-smoking interactions, two found evidence of an interaction. In Ambrosone et al.'s study, adjusted relative risks for Val carriers vs. Ile/Ile homozygotes among nonsmokers, light smokers (

The numbers analyzed in the studies of genotype-smoking interactions were small, and interpretation is difficult because of differences in the way in which interactions were assessed (stratifying by smoking status or genotype, or using a single reference group of smoking status and genotype combined) and in categorization of smoking status. For example, the interaction patterns observed by Ambrosone et al. Or Ishibe et al. would not be detectable by using an ever/never smoking categorization, as has been used in other studies.

Polychlorinated biphenyls (PCBs).

PCBs have been linked to breast cancer risk because of their estrogenic and tumor-promoting properties. In the Nurses' Health Study, a modest interaction between the Ile462Val polymorphism and plasma PCBs was found for postmenopausal, but not premenopausal, breast cancer. Among postmenopausal subjects, the adjusted relative risk for Val carriers in the upper tertile of plasma PCB levels, compared with Ile/Ile homozygotes in the lowest PCB tertile, was 2.78 (95% CI: 0.99, 7.82, p for interaction = 0.05). There was no interaction between PCBs and 3801T-C. In a subset of a study in western New York, Val carriers with an above-median PCB body burden had an increased risk compared with Ile/Ile homozygotes with a below-median PCB burden (adjusted RR = 2.9, 95% CI: 1.18, 7.45; p for interaction = 0.13).

Alcohol.

Basham et al. reported no interactions between Ile462Val or Thr461Asp polymorphisms and alcohol consumption. However, results were not shown.

Gene-gene interactions

CYP1A1 and glutathione S-transferase (GST) gene activities may be interrelated. The GST genes belong to the Ah gene battery, since GST is one of six enzymes regulated by the aryl hydrocarbon receptor. In human B-cell lines, absence of GSTM1 was associated with induction of high levels of CYP1A1 messenger RNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin, and presence of GSTM1 was associated with induction of low levels. Four breast cancer studies found no evidence of a CYP1A1-GSTM1 interaction, although CYP1A1-GSTM1 genotype combinations have been associated with age at presentation. In two relatively small studies assessing CYP1A1-GSTT1 genotype combinations, risk estimates were not significant, and tests for interaction were not reported. Another study found no significant differences in combined CYP1A1 3801T-C, GSTM1, and GSTT1 genotype frequencies between breast cancer patients and controls.

CYP17, CYP19, and catechol-O-methyltransferase (COMT) are involved in steroid hormone metabolism. One study found an increased breast cancer risk associated with the presence of two "high-risk" genotypes, defined as homozygosity for the CYP1A1 3801C, CYP17 A2, or COMT low-activity alleles (RR = 3.5, 95% CI: 1.06, 12.04), but no test for interaction was conducted. In another study, 3801T/T homozygotes carrying the CYP19 (TTTA)7(?3bp) allele had increased risk of estrogen-receptor-positive breast cancer (adjusted RR = 3.00, 95% CI: 1.56, 5.74) compared with women carrying the 3801C variant but not the CYP19 (TTTA)7(?3bp) allele.

Conclusions and Recommendation for Research

The CYP1A1 3801C variant is more common than the Val variant. Both variants occur more frequently in Asian than in White populations. The 3205C variant has been observed in African-Americans only, and little data are available on the geographic or ethnic distribution of the Thr461Asp polymorphism. The 3205T-C and Thr461Asp polymorphisms should be investigated in African, Asian, and Hispanic populations. The functional significance of all four polymorphisms is unclear, which could be due to the small sample sizes of most studies. Further investigation is warranted.

No consistent associations between breast cancer and CYP1A1 polymorphisms were found. While meta-analyses have greater power and precision for detecting gene-disease associations, our meta-analyses were limited by different genotype categorizations between studies. For the purposes of future meta-analyses, authors should provide results for all genotypes separately.

The 3801T-C and Ile462Val polymorphisms may modify the smoking-disease association, although the evidence is limited and inconsistent. A similar "inverse dose effect" has been observed in studies of CYP1A1, smoking, and lung cancer, and it has been suggested that the genetic variant might confer increased sensitivity to lower levels of exposure. Additional investigation is needed. The Val variant may interact with PCB levels to affect breast cancer risk, but confirmation is necessary. There was no evidence that GSTM1 or GSTT1 and CYP1A1 genotypes have a joint effect on disease risk. Studies suggesting interactions with CYP17, CYP19, and COMT should be replicated. Interpreting the studies of interaction was difficult because of the different approaches used; adopting a more unified approach in future studies would aid interpretation and synthesis of evidence.

Studies are needed to explore joint effects on breast cancer risk of the CYP1A1 genotype and 1) sources of PAH exposure other than tobacco, 2) markers of exposure to endogenous estrogens, 3) exposure to exogenous estrogens, 4) other lifestyle factors that influence hormone levels, 5) other genes encoding enzymes involved in PAH metabolism, and 6) other genes involved in hormonal biosynthesis. To detect gene-environment or gene-gene interactions, future studies must be large, and pooled analyses should be considered.

Comments and Analysis

My insight into this HuGE review are limited to the connections between the health outcomes and the genetic epidemiology study. The study found no association between breast cancer risk and Cytochrome P450 gene variants, which precludes making an correlations between breast cancer and this gene. Estrogen, which was indicated in the paper as an environmental cause of breast cancer, is not discussed in detail with respect to the Cytochrome P450 gene. I agree with their conclusions in that future studies must be done to detect gene-environment and gene-gene interactions. Overall the methodology is sound.