Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes.

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

Gender-related differences in response to mutagens and carcinogens.

The incidences of many cancers can be very different in men and women. Besides differences in exposures to putative causative agents, it is plausible that both genetic and epigenetic effects play roles in these differences. In addition, gender-specific lifestyle and behavioural factors may modulate the effects of exposure to genotoxins. This commentary focuses on several aspects of gender-related differences in responses to mutagens and carcinogens, including sensitivity to chromosome damage, the contribution of genotypic variation and the role of DNA methylation. It is concluded that the reasons for gender differences in cancer susceptibility remain largely unknown in many cases, and the subject deserves more attention and study.

Comparison of biomarkers in workers exposed to 2,4,6-trinitrotoluene.

2,4,6-Trinitrotoluene (TNT) is an important occupational and environmental pollutant. In TNT-exposed humans, notable toxic manifestations have included aplastic anaemia, toxic hepatitis, cataracts, hepatomegaly, and liver cancer. Therefore, methods were developed to biomonitor workers exposed to TNT. The workers were employed in a typical ammunition factory in China. The external dose (air levels and skin exposure), the internal dose (urinary metabolites), the biologically effective dose (haemoglobin adducts, urinary mutagenicity), biological effects (chromosomal aberrations and health effects), and individual susceptibility (genotypes of xenobiotic-metabolizing enzymes) were determined. Haemoglobin-adducts of TNT, 4-amino-2,6-dinitrotoluene (4ADNT) and 2-amino-4,6-dinitrotoluene (2ADNT), and the urinary metabolites of TNT, 4ADNT and 2ADNT, were found in all workers and in some controls. The levels of the haemoglobin-adducts or the urinary metabolites correlated weakly with the skin or air levels of TNT. The urinary mutagenicity determined in a subset of workers correlated strongly with the levels of 4ADNT and 2ADNT in urine. The haemoglobin-adducts correlated moderately with the urinary metabolites and with the urinary mutagenicity. The genotypes of glutathione S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) were determined. In general, the genotypes did not significantly influence the haemoglobin-adduct levels and the urine metabolite levels. However, TNT-exposed workers who carried the NAT1 rapid acetylator genotype showed an increase in urinary mutagenicity and chromosomal aberrations as compared with slow acetylators. The haemoglobin adduct 4ADNT was significantly associated with a risk of hepatomegaly, splenomegaly and cataract; urine metabolites and genotypes were not associated with health effects. These results indicate that a set of well-selected biomarkers may be more informative regarding exposure and effect than routinely performed chemical measurements of pollutants in the air or on the skin.

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years.

BACKGROUND: A genetic component of early-onset lung cancer has been suggested. The role of metabolic gene polymorphisms has never been studied in young lung cancer cases. Phase 1 and Phase 2 gene polymorphisms are involved in tobacco carcinogens' metabolism and therefore in lung cancer risk. METHODS: The effect of metabolic gene polymorphisms on lung cancer at young ages was studied by pooling data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. All primary lung cancer cases of both sexes who were Caucasian and

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women.

A case-control study was performed to assess the potential influence of CYP19 Arg(264)Cys and CYP1B1 Leu(432)Val polymorphisms on breast cancer risk in a series of Korean breast cancer patients and controls. The results suggest that the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95% CI=1.1-2.2), especially in association with alcohol consumption (P for interaction=0.04), whereas the CYP1B1 Leu(432)Val polymorphism appears to play no role here.

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Lack of interaction between asbestos exposure and glutathione S-transferase M1 and T1 genotypes in lung carcinogenesis.

An interaction between occupational carcinogens and genetic susceptibility factors in determining individual lung cancer risk is biologically plausible, but the interpretation of available studies are limited by the small number of exposed subjects. We selected from the international database on Genetic Susceptibility and Environmental Carcinogens the studies of lung cancer that included information on metabolic polymorphisms and occupational exposures. Adequate data were available for asbestos exposure and GSTM1 (five studies) and GSTT1 (three studies) polymorphisms. For GSTM1, the pooled analysis included 651 cases and 983 controls. The odds ratio (OR) of lung cancer was 2.0 [95% confidence interval (CI) 1.4-2.7] for asbestos exposure and 1.1 (95% CI 0.9-1.4) for GSTM1-null genotype. The OR of interaction between asbestos and GSTM1 polymorphism was 1.1 (95% CI 0.6-2.1) based on 54 cases and 53 controls who were asbestos exposed and GSTM1 null. The case-only approach, which was based on 869 lung cancer cases and had an 80% power to detect an OR of interaction of 1.56, also provided lack of evidence of interaction. The analysis of possible interaction between GSTT1 polymorphism and asbestos exposure in relation to lung cancer was based on 619 cases. The prevalence OR of GSTT1-null genotype and asbestos exposure was 1.1 (95% CI 0.6-2.0). Our results do not support the hypothesis that the risk of lung cancer after asbestos exposure differs according to GSTM1 genotype. The low statistical power of the pooled analysis for GSTT1 genotypes hampered any firm conclusion. No adequate data were available to assess other interactions between occupational exposures and metabolic polymorphisms.

CYP1A1 levels in lung tissue of tobacco smokers and polymorphisms of CYP1A1 and aromatic hydrocarbon receptor.

Induction of a polycyclic aromatic hydrocarbon-metabolizing cytochrome P450 isoform CYP1A1 is regulated by aromatic hydrocarbon receptor (AHR). High inducibility of CYP1A1, possibly due to genetic polymorphisms, has been considered to be a risk factor for lung cancer in tobacco smokers. The relationship between low or high pulmonary expression of CYP1A1 and polymorphic genotypes of CYP1A1 and AHR was investigated in 73 active smokers. CYP1A1 expression was determined in surgical lung samples by measuring ethoxyresorufin O-deethylase (EROD) activity and by immunostaining for CYP1A1 protein. The most common allelic variants of CYP1A1 and AHR in Finns, i.e. the MspI variant (CYP1A1*2A), I462V variant (CYP1A1*2B), and -459C to T variant of CYP1A1 and the R554K variant (AHR*2) of AHR were studied using polymerase chain reaction based methods. EROD activity correlated positively with the daily cigarette consumption (r = 0.45). There was additional variation in EROD activity independent of the amount of smoking e.g. among those who smoked one pack per day until the day of operation, EROD activity ranged from 4-142 (median 48) pmol/min/mg. The frequencies of the MspI, 462V, and -459T variant alleles of CYP1A1 and 554K variant allele of AHR were 0.158, 0.055, 0.055 and 0.075, respectively. No differences were observed in the frequencies of polymorphic genotypes between the smokers with low and those with high expression, when the relationship was studied using a regression analysis adjusted for cigarette consumption. Our results thus indicate that the interindividual variation of CYP1A1 levels in smokers' lung tissue is not attributable to genetic polymorphisms of CYP1A1 or AHR tested in this study.

Relationship between the Val158Met polymorphism of catechol O-methyl transferase and breast cancer.

A case-control study was performed to assess the potential influence of catechol O-methyl transferase (COMT) genotype on the risk of breast cancer in Korean women. One hundred and sixty-three histologically confirmed incident breast cancer cases and 163 age- and menopausal status-matched control individuals with no present or previous history of cancer were selected as study subjects. COMT genetic polymorphism was determined by gel electrophoresis after NlaIII enzyme digestion of amplified DNA. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Women with at least one COMT lower enzyme activity associated allele (COMT-L) were at elevated risk for breast cancer (OR = 1.7, 95% CI = 1.04-2.78) compared with those homozygous for high enzyme activity associated COMT-H alleles. Among women with low (> or = 23.1) body mass index the COMT-L allele containing genotypes posed a marginally significant increased risk of breast cancer compared to the COMT-HH genotype (OR = 1.8, 95% CI = 0.95-3.48). Women with at least one COMT-L allele who had experienced a full-term pregnancy when aged over 30 years or were nulliparous had 2.7-fold increased risk; however, this increase did not reach statistical significance (OR = 2.7, 95% CI = 0.64-11.35). Furthermore, never-drinking and never-smoking women with at least one COMT-L allele were at increased risk of breast cancer compared to those with COMT-HH genotype with ORs of 2.0 (95% CI = 1.23-3.38) and 1.7 (95% CI = 1.04-2.62), respectively. These results are consistent with studies showing that COMT genotype of lower enzyme activity might be related to increase in risk of breast cancer, and extend this finding to Korean women.

Chromosomal aberrations in peripheral lymphocytes of train engine drivers.

Studies of Swedish railway employees have indicated that railroad engine drivers have an increased cancer morbidity and incidence of chronic lymphatic leukemia. The drivers are exposed to relatively high magnetic fields (MF), ranging from a few to over a hundred microT. Although the possible genotoxic potential of MF is unclear, some earlier studies have indicated that occupational exposure to MF may increase chromosome aberrations in blood lymphocytes. Since an increased level of chromosomal aberrations has been suggested to predict elevated cancer risk, we performed a cytogenetic analysis on cultured (48 h) peripheral lymphocytes of Swedish train engine drivers. A pilot study of 18 engine drivers indicated a significant difference in the frequency of cells with chromosomal aberrations (gaps included or excluded) in comparison with seven concurrent referents (train dispatchers) and a control group of 16 office workers. The engine drivers had about four times higher frequency of cells with chromosome-type aberrations (excluding gaps) than the office workers (P < 0.01) and the dispatchers (P < 0.05). Seventy-eight percent of the engine drivers showed at least one cell per 100 with chromosome-type aberrations compared with 29% among the dispatchers and 31% among the office workers. In a follow-up study, another 30 engine drivers showed an increase (P < 0.05) in the frequency of cells with chromosome-type aberrations (gaps excluded) as compared with 30 referent policemen. Sixty percent of the engine drivers had one or more cells (per 100 cells) with chromosome-type aberrations compared with 30% among the policemen. In conclusion, the results of the two studies support the hypothesis that exposure to MF at mean intensities of 2-15 microT can induce chromosomal damage.

Polymorphic catechol-O-methyltransferase gene and breast cancer risk.

We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index (30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (

Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk.

Superoxide dismutases play a key role in the detoxification of superoxide radicals and thus protect cells from damage induced by free radicals. Within mitochondria manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species. Polymorphism in the mitochondrial targeting sequence of MnSOD has recently been associated with risk of breast cancer. We examined this in a study population consisting of 483 breast cancer cases and 482 controls, all of Finnish Caucasian origin. Odds ratios (OR) and 95% confidence intervals (95% CIs) were estimated by unconditional logistic regression. MnSOD genotypes containing the variant A allele were found to be associated with a 1.5-fold (95% CI 1.1-2.0) increased risk of breast cancer compared with those with the homozygous wild-type genotype (MnSOD VV). This finding supports the proposal that MnSOD genotypes may modify individual breast cancer risk.

Metabolic genetic polymorphisms and susceptibility to lung cancer.

Activity of some enzymes implicated in the metabolism of tobacco carcinogens presents a great variability between individuals due to the existence of a polymorphism in gene coding for these enzymes. Individual susceptibility to develop lung cancer could therefore depend not only on exposure to tobacco smoking, but also on genetic capacity to activate or inactivate tobacco carcinogens. This article summarizes the state of knowledge on metabolic polymorphisms and lung cancer susceptibility, and opens the discussion on the future direction of this promising way of research.

Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer.

This study was undertaken to examine if glutathione S-transferase (GST) M1, M3, P1, and T1 genotypes affected breast cancer risk in Finnish women. The study population consisted of 483 incident breast cancer cases and 482 healthy population controls. Genotyping analyses were performed by PCR-based methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected risk factors for breast cancer. When the genes were studied separately, the only significant finding was between GSTM1 null genotype and postmenopausal breast cancer risk (OR, 1.49; 95% CI, 1.03-2.15). Conversely, when the potential combined effects of the at-risk genotypes were examined, significant associations were observed only among premenopausal women. Although only a moderate risk of breast cancer was seen for premenopausal women concurrently carrying the GSTM3*B allele containing genotypes and the GSTP1 Ile/ Ile genotype (OR, 2.07; 95% CI, 1.02-4.18), the risk rose steeply if they simultaneously lacked the GSTT1 gene (OR, 9.93, 95% CI, 1.10-90.0). A borderline significant increase in the risk of breast cancer was also seen for premenopausal women with the combination of GSTM1 null, GSTP1 Ile/Ile, and GSTT1 null genotypes (OR, 3.96; 95% CI, 0.99-15.8). Our findings support the view that GST genotypes contribute to the individual breast cancer risk, especially in certain combinations.

Importance of genetic polymorphisms of drug-metabolizing enzymes for the interpretation of biomarkers of exposure to styrene.

The objective of this study was to test the infiuence of genetic polymorphisms for metabolic enzymes (CYP2E1, mEH, GSTM1 and GSTT1) implicated in the biotransformation of styrene in humans on the interpretation of urinary biomarkers of exposure. Thirty workers from a fibreglass-reinforced plastics factory took part in the study. Ambient styrene concentration was determined during the whole workshift by passive sampling. Urine was collected at the end of the shift for the determination of mandelic acid (MA) and phenylglyoxylic acid (PGA) (major biotransformation pathway), N-acetyl-S-(1-phenyl-2-hydroxy)ethyl-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxy)ethyl-L-cysteine (M2) (minor metabolic pathway) and creatinine. The average airborne styrene concentration of 18.2 ppm (range: 0.9-68.9 ppm) was very close to the current threshold limit value (TLV-TWA) recently adjusted by ACGIH from 50 to 20 ppm. There was a better correlation between external and internal exposure as estimated by urinary MA + PGA (r=0.92; p<0.0001) compared with urinary M1 + M2 (r=0.74; p<0.0001). To investigate to what extent genetic polymorphisms in metabolic enzymes could explain interindividual variations observed in the concentration of urinary biomarkers related to a given external exposure, two 'metabolic indexes' (derived from the ratio between the sum of urinary metabolites for a specific pathway and ambient styrene concentration) were calculated for each worker and compared for different allelic combinations. Monovariate analyses showed that GSTM1 polymorphism was clearly the most significant parameter infiuencing urinary concentrations of mercapturic acids. Based on GSTM1 allelic status, two different biological exposure indexes (BEIs) for M1 + M2 in post-shift urinary samples corresponding to a 20 ppm styrene concentration are proposed (GSTM1null: 1330 µg g(-1) creatinine, GSTM1+: 2878 µg g(-1) creatinine). Multivariate regression analyses were also performed and revealed that the presence of the rare CYP2E1*1B allele linked to TaqI polymorphism (A1/A2) was associated with increased urinary concentrations of metabolites from both pathways. Two previously described polymorphisms for the EPHX gene were also tested but seemed not really relevant for interpretation of biomarkers. In conclusion, while CYP2E1 genotyping, particularly assessment of the CYP2E1*1B allelic status, is useful for a more accurate interpretation of the concentration of urinary biomarkers, GSTM1 genotyping is absolutely necessary when considering a biological monitoring programme based on determination of urinary mercapturic acids.

CYP2D6 gene polymorphism in caucasian smokers: lung cancer susceptibility and phenotype-genotype relationships.

Individual susceptibility to smoking-related cancers is proposed to partly depend on a genetically determined ability to metabolise tobacco carcinogens. We previously reported on the association between the activity of the xenobiotic-metabolising enzyme CYP2D6 and lung cancer risk in a hospital-based case-control study among French Caucasian smokers. Here we extended the study to address the effect of four gene-inactivating mutations (CYP2D6(*)3, (*)4, (*)5 and (*)16) and the gene duplication of the CYP2D6 gene (CYP2D6(*)2x2 or CYP2D6(*)1x2) on lung cancer risk in the same population (150 patients with primary lung carcinoma of squamous cell or small cell histology and 172 controls). The risk of lung cancer associated with the CYP2D6 poor metaboliser genotype (odds ratio 1.5, 95% confidence interval 0.5-4.3) did not differ from that in the reference category of extensive metaboliser and ultra-rapid metaboliser genotypes combined. Lung cancer risks for the CYP2D6 PM genotype amongst light smokers (tobacco consumption 20 g/day) were not significantly different. The present findings agree with the discrepancy between the phenotype-based and genotype-based studies indicated by the recent meta-analyses.

Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract.

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH(3) and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH(3) genotype was not associated with UAT cancer. In contrast, a 2-fold risk of oral cavity/pharyngeal (OR = 2.0, 95% CI 1.0-3.9) and laryngeal (OR = 1.8, 95% CI 1.0-3.5) cancers was observed for carriers of the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/pharyngeal cancer (OR = 2.6, 95% CI 1.0-6. 6). The effects of ADH(3) or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers (>80 g/day) with the CYP2E1 DraI C allele (OR = 5.8, 95% CI 1.9-18.2) or the CYP2E1 RsaI c2 allele (OR = 7.2, 95% CI 1.4-38.2) compared with lighter drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings.

Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk.

To evaluate the potential association between GSTM1 and GSTT1 genotypes and development of breast cancer, a hospital based case-control study was conducted in a South Korean study population consisting of 189 histologically confirmed incident breast cancer cases and their 189 age-matched control subjects with no present or previous history of cancer. A multiplex polymerase chain reaction method was used for the genotyping analyses and statistical evaluations were performed by unconditional logistic regression model. The GSTM1 null genotype was significantly associated with breast cancer risk in premenopausal women [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1-3.7], but not in the postmenopausal women (OR = 0.9, 95% CI = 0.5-1.9), nor in all women grouped together (OR = 1.3, 95% CI = 0.8-1.1). The GSTT1 null genotype posed a similar risk of breast cancer with an OR of 1.6 (95% CI = 1.0-2.5) for the total breast cancer group, OR of 1.7 (95% CI = 0.9-3.2) for pre-menopausal women, and OR of 1.3 (95% CI = 0.6-2.8) for post-menopausal women. The breast cancer risk associated with concurrent lack of both GSTM1 and GSTT1 genes was 2.2 (95% CI = 1.1-4.5), and the risk increased as the number of null genotype increased (P for trend = 0.03). When the data were stratified by the known risk factors of breast cancer, a significant interaction was observed between the GSTM1 genotypes and alcohol consumption (P for interaction = 0.03). An especially remarkable risk of breast cancer was observed for alcohol-consuming premenopausal women lacking both the GSTM1 and GSTT1 genes (OR = 5.3, 95% CI = 1.0-27.8) compared to those with both of the genes. Our findings thus suggest a novel gene-environment interaction which plays an important role in the individual susceptibility to breast cancer. p6