[Show abstract][Hide abstract] ABSTRACT: Genetically determined factors that alter the metabolism of tobacco carcinogens can influence an individual's susceptibility to bladder cancer. The associations between the genotypes of glutathione S-transferase (GST) M1, GSTP1, GSTT1 and N-acetyltransferase (NAT) 1 and the phenotypes of NAT2 and cytochrome P450 (CYP) 1A2 and bladder cancer risk were examined in a case-control study involving 731 bladder cancer patients and 740 control subjects in Los Angeles County, California. Individual null/low-activity genotypes of GSTM1, GSTT1 and GSTP1 were associated with a 19-48% increase in odds ratio (OR) of bladder cancer. The strongest association was noted for GSTM1 [OR for the null genotype = 1.48, 95% confidence interval (CI) = 1.19-1.83]. When the three GST genes were examined together, there was a monotonic, statistically significant association between increasing number of null/low-activity genotypes and risk (P for trend = 0.002). OR (95% CI) for one and two or more null/low-activity GST genotypes was 1.42 (1.12-1.81) and 1.71 (1.25-2.34), respectively, relative to the absence of null/low-activity GST genotype. NAT2 slow acetylation was associated with doubled risk of bladder cancer among individuals with known high exposures to carcinogenic arylamines (OR = 2.03, 95% CI = 1.12-3.69, P = 0.02). The effect of NAT2 slow acetylation was even stronger in the presence of two or more null/low-activity GST genotypes. There were no associations between bladder cancer risk and NAT1 genotype or CYP1A2 phenotype.
[Show abstract][Hide abstract] ABSTRACT: Discovery and functional evaluation of biologically significant regulatory single nucleotide polymorphisms (SNP) in carcinogen metabolism genes is a difficult challenge because the phenotypic consequences may be both transient and subtle. We have used a gene expression screening approach to identify a functional regulatory SNP in glutathione S-transferase M3 (GSTM3). Anttila et al. proposed that variation in GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression variation, we measured GSTM3 expression in lymphoblast cells from a human Centre d'Etude du Polymorphisme Humain family and observed a low expression phenotype. Promoter sequencing revealed two novel GSTM3 promoter SNPs: A/C and A/G SNPs, 63 and 783 bp upstream of the codon 1 start site, respectively. In this pedigree, the two children homozygous for the -63C/C genotype had 8-fold lower GSTM3 expression relative to the two children with the -63A/A genotype, with no association between A-783G SNP and GSTM3 expression. Further evaluation using genotyped glioma cell lines and with luciferase reporter constructs showed that the -63C allele was associated with lower GSTM3 expression (P < 0.0001 and P < 0.003). RNA pol II chromatin immunoprecipitation was combined with quantitative probed-based allelic discrimination genotyping to provide direct evidence of a 9-fold reduced RNA pol II binding capacity for the -63C allele. These results show that the GSTM3 -63C allele strongly affects gene expression in human cell lines and suggests that individuals who carry the low expression allele may be deficient in glutathione transferase catalyzed biological functions.
Cancer Research 02/2005; 65(1):99-104. · 8.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous epidemiological studies of fruit and vegetable intake and bladder cancer risk have yielded inconsistent results, especially with respect to the role of cigarette smoking as a possible modifier of the diet-bladder cancer association. A population-based case-control study was conducted in nonAsians of Los Angeles, California, which included 1,592 bladder cancer patients and an equal number of neighborhood controls matched to the index cases by sex, date of birth (within 5 years) and race between January 1, 1987 and April 30, 1996. Information on smoking, medical and medication history, and intake frequencies of food groups rich in preformed nitrosamines, vitamins A and C and various carotenoids, were collected through in-person, structured interviews. Beginning in January 1992, all case patients and their matched control subjects were asked for a blood sample donation at the end of the in-person interviews for measurements of 3- and 4-aminobiphenyl (ABP) hemoglobin adducts, and glutathione S-transferases M1/T1/P1 (GSTM1/T1/P1) and N-acetyltransferase-1 (NAT1) genotypes. Seven hundred seventy-one (74%) case patients and 775 (79%) control subjects consented to the blood donation requests. In addition, all case patients and matched control subjects were asked to donate an overnight urine specimen following caffeine consumption for measurements of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) phenotypes. Urine specimens were collected from 724 (69%) case patients and 689 (70%) control subjects. After adjustment for nondietary risk factors including cigarette smoking, there were strong inverse associations between bladder cancer risk and intake of dark-green vegetables [p value for linear trend (p) = 0.01], yellow-orange vegetables (p = 0.01), citrus fruits/juices (p = 0.002) and tomato products (p = 0.03). In terms of nutrients, bladder cancer risk was inversely associated with intake of both total carotenoids (p = 0.004) and vitamin C (p = 0.02). There was a close correlation (r = 0.58, p = 0.0001) between intakes of total carotenoids and vitamin C in study subjects. When both nutrients were included in a multivariate logistic regression model, only total carotenoids exhibited a residual effect that was of borderline statistical significance (p = 0.07 and p = 0.40 for total carotenoids and vitamin C, respectively). Cigarette smoking was a strong modifier of the observed dietary effects; these protective effects were confined largely to ever smokers and were stronger in current than ex-smokers. Smokers showed a statistically significant or borderline statistically significant decrease in 3- and 4-aminobiphenyl (ABP)-hemoglobin adduct level with increasing intake of carotenoids (p = 0.04 and 0.05, respectively). The protective effect of carotenoids on bladder cancer seemed to be influenced by NAT1 genotype, NAT2 phenotype and CYP1A2 phenotype; the association was mainly confined to subjects possessing the putative NAT1-rapid, NAT2-rapid and CYP1A2-rapid genotype/phenotype. The carotenoid-bladder cancer association was not affected by the GSTM1, GSTT1 and GSTP1 genotypes.
International Journal of Cancer 07/2004; 110(3):417-23. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A decreased incidence of squamous cell carcinoma of the head and neck (SCCHN) associated with fruit and vegetable intake may act through chemopreventive compounds, which may be more available to persons homozygous for the deletion genotypes of the glutathione S-transferase (GST). We evaluated interactions between fruits and vegetables and GSTM1 and GSTT1 on incidence of SCCHN using data from a case-control study of 149 cases and 180 age- and gender-matched controls. After adjustment for age, gender, race, tobacco and alcohol use, weekly consumption of four or more servings of raw vegetables was inversely associated with SCCHN [odds ratio (OR) = 0.66, 95% confidence intervals (CI) 0.30-1.3]. Contrary to expectation, relatively high intake of cooked vegetables (14 or more weekly servings) and legumes (two or more weekly servings) were associated with increased incidence (OR = 2.5, 95% CI 1.1-6.0; OR = 2.5, 95% CI 1.2-5.2, respectively). In general, our results did not suggest a clear or consistent pattern of modification by GST genotypes of the association between foods and SCCHN. For example, eating cruciferous vegetables, foods of a priori interest, and having the GSTM1-deletion genotype was not associated with the expected reduction in incidence compared with abstaining from cruciferous vegetable intake and having the GSTM1-present genotype. Among non-consumers of cruciferous vegetables, the GSTM1-deletion genotype was inversely associated with SCCHN (OR = 0.55, 95% CI 0.07-4.2). Raw vegetables were associated with a reduction in incidence only among persons with the GSTM1-deletion genotype (OR = 0.69, 95% CI 0.29-1.6), whereas either factor alone had a null association. Future research of GST-diet interactions and SCCHN would benefit from larger, population-based studies.
[Show abstract][Hide abstract] ABSTRACT: Meat cooked at high temperatures contains potential carcinogenic compounds, such as heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Samples from a 2-week controlled feeding study were used to examine the relationship between the intake of mutagenicity from meat fried at different temperatures and the levels of mutagenicity subsequently detected in urine, as well as the influence of the genotype of drug metabolizing enzymes on urinary mutagenicity. Sixty subjects consumed ground beef patties fried at low temperature (100 degrees C) for 1 week, followed by ground beef patties fried at high temperature (250 degrees C) the second week. Mutagenicity in the meat was assayed in Salmonella typhimurium TA98 (+S9), and urinary mutagenicity was determined using Salmonella YG1024 (+S9). Genotypes for NAT1, NAT2, GSTM1, and UGT1A1 were analyzed using blood samples from the subjects. Meat fried at 100 degrees C was not mutagenic, whereas meat fried at 250 degrees C was mutagenic (1023 rev/g). Unhydrolyzed and hydrolyzed urine samples were 22x and 131x more mutagenic, respectively, when subjects consumed red meat fried at 250 degrees C compared with red meat fried at 100 degrees C. We found that hydrolyzed urine was approximately 8x more mutagenic than unhydrolyzed urine, likely due to the deconjugation of mutagens from glucuronide. The intake of meat cooked at high temperature correlated with the mutagenicity of unhydrolyzed urine (r = 0.32, P = 0.01) and hydrolyzed urine (r = 0.34, P = 0.008). Mutagenicity in unhydrolyzed urine was not influenced by NAT1, NAT2, or GSTM1 genotypes. However, a UGT1A1*28 polymorphism that reduced UGT1A1 expression and conjugation modified the effect of intake of meat cooked at high temperature on mutagenicity of unhydrolyzed urine (P for interaction = 0.04). These mutagenicity data were also compared with previously determined levels of HCAs (measured as MeIQx, DiMeIQx, and PhIP) and polycyclic aromatic hydrocarbons (PAHs) in the meat, levels of HCAs in the urine, and CYP1A2 and NAT2 phenotypes. The levels of mutagenicity in the meat fried at low and high temperatures correlated with levels of HCAs, but not levels of PAHs, in the meat. Also, levels of mutagenicity in unhydrolyzed urine correlated with levels of MeIQx in unhydrolyzed urine (r = 0.36; P = 0.01), and the levels of mutagenicity of hydrolyzed urine correlated with levels of MeIQx (r = 0.34; P = 0.01) and PhIP (r = 0.43; P = 0.001) of hydrolyzed urine. Mutagenicity in unhydrolyzed urine was not influenced by either the CYP1A2 or NAT2 phenotype. The data from this study indicate that urinary mutagenicity correlates with mutagenic exposure from cooked meat and can potentially be used as a marker in etiological studies on cancer.
Environmental and Molecular Mutagenesis 02/2004; 43(1):53-74. · 3.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have previously reported permanent hair dye use to be a significant risk factor for bladder cancer in US women. We also have examined N-acetyltransferase-2 (NAT2) phenotype in relation to the hair dye-bladder cancer relationship, and found that the association is principally confined to NAT2 slow acetylators. In the present study, we assessed the possible modifying effects of a series of potential arylamine-metabolizing genotypes/phenotypes (GSTM1, GSTT1, GSTP1, NAT1, NAT2, CYP1A2) on the permanent hair dye-bladder cancer association, among female participants (159 cases, 164 controls) of the Los Angeles Bladder Cancer Study. Among NAT2 slow acetylators, exclusive permanent hair dye use was associated with a 2.9-fold increased risk of bladder cancer (95% CI = 1.2-7.5). The corresponding relative risk in NAT2 rapid acetylators was 1.3 (95% CI = 0.6-2.8). Frequency- and duration-related dose-response relationships confined to NAT2 slow acetylators were all positive and statistically significant. No such associations were noted among NAT2 rapid acetylators. Among CYP1A2 'slow' individuals, exclusive permanent hair dye use was associated with a 2.5-fold increased risk of bladder cancer (95% CI = 1.04-6.1). The corresponding risk in CYP1A2 'rapid' individuals was 1.3 (95% CI = 0.6-2.7). Frequency- and duration-related dose-response relationships confined to CYP1A2 'slow' individuals were all positive and statistically significant. No such associations were noted among CYP1A2 'rapid' individuals. Among lifelong non-smoking women, individuals exhibiting the non-NAT1*10 genotype showed a statistically significant increase in bladder cancer risk associated with exclusive permanent hair dye use (OR = 6.8, 95% CI = 1.7-27.4). The comparable OR in individuals with the NAT1*10 genotype was 1.0 (95%CI = 0.2-4.3). Similarly, all frequency- and duration-related dose-response relationships confined to individuals possessing the non-NAT1*10 genotype were positive and statistically significant. On the other hand, individuals of NAT1*10 genotype exhibited no such associations.
[Show abstract][Hide abstract] ABSTRACT: Inter-individual differences in DNA repair capacity have been demonstrated using a variety of phenotypic assays, including reduced repair among patients with squamous cell carcinoma of the head and neck (SCCHN). The XRCC1 DNA repair gene may facilitate DNA strand break and base excision repair. A recent case-control study of SCCHN reported associations with two polymorphisms of the XRCC1 including the exon 6, 194Arg/Arg genotype and the exon 10, 399 Gln/Gln genotype. We conducted an analysis of these two XRCC1 polymorphisms using data from a case-control study of SCCHN. Among white subjects, we found a weak elevation in risk associated with the Arg194Trp polymorphism [odds ratio (OR)=1.3; 95% confidence interval (CI)=0.6-2.9] and a decreased risk for the Arg399Gln polymorphism (OR=0.6; CI=0.4-1.1). We found a markedly decreased odds ratio for the Gln/Gln genotype among whites (OR=0.1; CI=0.04-0.6) and blacks (OR=0.01; CI=0.0004-0.3). We also found a suggestion of an interaction between the Arg194Trp and Arg399Gln polymorphisms and tobacco use. Additional epidemiologic and functional studies are needed to resolve the importance of these XRCC1 polymorphisms in SCCHN.
Cancer Letters 05/2002; 178(2):181-6. · 5.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Squamous cell carcinoma of the head and neck (SCCHN), including the oral cavity, pharynx and larynx, is an excellent tumor model to evaluate gene-environment interactions, including alcohol and alcohol-metabolizing enzymes such as alcohol dehydrogenase (ADH). We conducted a hospital-based case-control study including 182 cases with newly diagnosed SCCHN and 202 controls with non-neoplastic conditions of the head and neck that required surgery. The joint effects of lifetime alcohol use and the presence of the ADH3 'rapid' allele (ADH3(*)1) was evaluated in relation to the risk of SCCHN. Logistic regression was used to estimate the interaction between alcohol use and ADH3 genotype with adjustment for tobacco use, age, sex and race. The interaction was evaluated on both the multiplicative and additive scales. The risk of SCCHN was increased nearly 6-fold with consumption of 40 or more alcoholic beverages per week [odds ratio (OR) = 5.9; 95% confidence interval (CI) = 2.0-17.7; adjusted for age, sex, race and years of tobacco use]. We did not find any increase in risk for ADH3*1 homozygotes (OR = 0.9; CI = 0.4-1.9) or heterozygotes (OR = 0.8; CI = 0.4-1.7) relative to ADH3(*)2 homozygotes. There was no suggestion of an interaction between any alcohol use variable and the ADH3(*)1 genotype. For example, the interaction term, including the continuous variable average number of drinks per week and the ADH3 genotypes, was non-significant (P = 0.22). The study does not indicate an important role for the ADH3 (*)1 polymorphism in SCCHN, but larger numbers are needed to more precisely estimate the interaction, if any, with ADH3.
[Show abstract][Hide abstract] ABSTRACT: In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression products of either of the N-acetyltransferase genes, NAT1 or NAT2. This conjugation reaction can result in either activation or detoxication of these carcinogens depending on the tissue involved. Recent studies suggest that polymorphisms in NAT1 or NAT2 may modulate cancer risk. To determine if genetic differences in NAT1 and NAT2 could alter risk of gastric cancer, we tested for the presence of polymorphic N-acetyltransferase alleles (both NAT1 and NAT2) in a preliminary study of 94 gastric adenocarcinoma patients and 112 control subjects from North Staffordshire, England. We used established PCR protocols to genotype for NAT2 and NAT1 alleles (NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14; NAT1*3, NAT1* 4, NAT1*10, and NAT1*11), and implemented an oligonucleotide ligation assay (OLA) to test for low-activity NAT1 alleles [NAT1*14 (G560A), NAT1*15 (C559T), and NAT1*17 (C190T)]. No significant increased risk was observed for NAT2 acetylation genotypes. However, among all cases, we found that individuals inheriting a variant NAT1 allele, NAT1*10, have a significantly elevated risk for gastric cancer (OR = 2.2, 95% CI 1. 2-3.9, P < 0.01). Interestingly, the risk observed for NAT1*10 appears to be solely associated with advanced-stage tumors (OR = 4.8, P < 0.001), suggesting a possible role in progression to advanced disease. This preliminary finding needs confirmation in a larger, detailed epidemiological study.
International Journal of Cancer 09/2000; 87(4):507-11. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Squamous cell carcinoma of the head and neck (SCCHN), including the oral cavity, pharynx, and larynx, provides an ideal tumor model to investigate gene-environment interaction. We conducted a hospital-based case-control study including 182 cases with newly diagnosed SCCHN and 202 controls with nonneoplastic conditions of the head and neck that required surgery. Lifetime tobacco use and risk of SCCHN were evaluated in relation to the polymorphisms of GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1. The main effects of genotype were associated with a slightly increased risk of SCCHN for GSTP1 [age-, race-, and sex-adjusted odds ratio (OR), 1.2; confidence interval (CI), 0.8-1.9], GSTT1 (OR, 1.2; CI, 0.7-2.3), and NAT1 (OR, 1.1; CI, 0.7-1.7). The joint effects of genotype combinations showed some excess risk for the combination of the GSTM1 null genotype and the CYP1A1 Ile/Val polymorphism (OR, 2.6; CI, 0.7-10.3). The analysis of the joint effects (interaction) of the "at-risk" genotypes and tobacco use did not reveal any interaction on either the multiplicative or additive scale for GSTM1, GSTP1, or CYP1A1. However, there was a suggestion of an interaction on the additive scale between the pack-years of tobacco use and the GSTT1 null genotype. The combined heterozygote and homozygote NAT1*10 genotypes also had a suggestive interaction with tobacco smoking history. The results of this study suggest a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.
[Show abstract][Hide abstract] ABSTRACT: Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer.
In 1989, a total of 32 898 individuals donated blood samples to a research specimen bank established in Washington County, MD. Genotypes of blood specimen DNA were determined for 110 of 115 women with incident cases of breast cancer diagnosed during the period from 1990 through 1995 and up to 113 of 115 control subjects. Associations between specific genotypes and the development of breast cancer were examined by use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65). For GSTP1, the data were suggestive of a trend of increasing risk with higher numbers of codon 105 valine alleles (compared with isoleucine alleles); a 1.97-fold increased risk of breast cancer (95% CI = 0.77-5.02) was associated with valine/valine homozygosity. The risk of breast cancer associated with the GSTT1 homozygous null genotype was 1.50 (95 % CI = 0.76-2.95). The risk of breast cancer increased as the number of putative high-risk genotypes increased (P for trend <.001) (OR = 3.77; 95% CI = 1.10-12.88 for a combined genotype of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity).
Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.
JNCI Journal of the National Cancer Institute 04/1998; 90(7):512-8. · 14.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT(LL)). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT(HL) and COMT(LL) genotypes were 1.30 [confidence interval (CI), 0.66-2.58] and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT(LL) women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93-5.11]. The association of COMT(LL) with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT(LL) was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.
Cancer Research 12/1997; 57(24):5493-7. · 8.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The major objective of this study was to investigate the expression of members of the raf family of proto-oncogenes during rat liver regeneration. The steady-state level of expression of both c-raf-1 and A-raf-1 increased three- to fivefold 18-24 h following partial hepatectomy, and it returned to basal levels by 72 h. Expression of c-myc and Ha-ras mRNA was increased at 3 and 18-24 h, respectively, confirming previous reports. Increased steady-state levels of c-raf-1, A-raf-1, and Ha-ras mRNA were also detected in hepatocytes isolated from rat liver 24 h after partial hepatectomy. Thus, elevated expression of the raf genes closely correlated with that of Ha-ras, beginning at 12 h and reaching maximal levels during the first peak of DNA synthesis following partial hepatectomy.
[Show abstract][Hide abstract] ABSTRACT: Mounting evidence suggests that catechol metabolites of estradici may contribute to the development of estrogen-induced cancers. O-Methyla- tion, catalyzed by catechol-O-methyltransferase (COMT), inactivates cat echol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity alÃeleof the enzyme (COMT1-1-).We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT"1' and COMT1-1-genotypes were 1.30 (confidence interval (CI), 0.66-2.58) and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT1'1-women had a greater than 2-fold increased risk of developing breast cancer (odds ratio (OR), 2.18; CI, 0.93-5.11). The association of COMT1-1-with the development of post- menopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT1-1'was combined with either glutathione S- transferase (GST) Ml null or with GSTP1 Ile-105-Val/Val-105-Val (inter mediate/low activity, respectively) genotypes, the risk for developing post- menopausal breast cancer was also significantly increased. Our findings suggest that the alÃeleencoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in cer tain women.