Green Tea Catechin Extract Supplementation Does Not Influence Circulating Sex Hormones and Insulin-Like Growth Factor Axis Proteins in a Randomized Controlled Trial of Postmenopausal Women at High Risk of Breast Cancer.

BACKGROUND: Consumption of green tea has been associated with reduced risk of breast cancer. Hormonal modulation has been suggested as one of the potential underlying mechanisms; however, it has yet to be fully elucidated in large, long-term human clinical trials. OBJECTIVE: We investigated the effects of decaffeinated green tea extract (GTE) on circulating sex hormones and insulin-like growth factor (IGF) proteins. METHODS: We conducted a placebo-controlled double-blind randomized clinical trial recruiting from 8 clinical centers in Minnesota. Participants were 538 healthy postmenopausal women randomly assigned to the GTE group (463 completed the study; mean age = 60.0 y) and 537 to the placebo group (474 completed; mean age = 59.7 y). Women in the GTE group orally took 4 decaffeinated capsules containing 1315 mg total catechins including 843 mg epigallocatechin-3-gallate daily for 1 y, whereas women in the placebo group took similar capsules containing no tea catechins. Blood sex hormones (estrone, estradiol, androstenedione, testosterone, and sex hormone-binding globulin) and IGF proteins (IGF-1 and IGF binding protein-3) were quantified at baseline and months 6 (for IGF proteins only) and 12, and were assessed as secondary outcomes of the study using a mixed-effect repeated-measures ANOVA model. RESULTS: Women in the GTE group had significantly higher blood total estradiol (16%; P = 0.02) and bioavailable estradiol (21%; P = 0.03) than in the placebo group at month 12. There was a statistically significant interaction between GTE supplementation and duration of treatment on estradiol and bioavailable estradiol (both Ps for interaction = 0.001). The catechol-O-methyltransferase genotype did not influence blood sex hormones before or after GTE supplementation. The circulating concentrations of IGF proteins were comparable between GTE and placebo groups at all 3 time points. CONCLUSION: These results suggest that a 12-mo GTE supplementation significantly increases circulating estradiol concentrations in healthy postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00917735.

Quantification of Hemoglobin and White Blood Cell DNA Adducts of the Tobacco Carcinogens 2-Amino-9H-pyrido[2,3-b]indole and 4-Aminobiphenyl Formed in Humans by Nanoflow Liquid Chromatography/Ion Trap Multistage Mass Spectrometry.

Aromatic amines covalently bound to hemoglobin (Hb) as sulfinamide adducts at the cysteine 93 residue of the Hb ß chain have served as biomarkers to assess exposure to this class of human carcinogens for the past 30 years. In this study, we report that 2-amino-9H-pyrido[2,3-b]indole (AαC), an abundant carcinogenic heterocyclic aromatic amine formed in tobacco smoke and charred cooked meats, also reacts with Hb to form a sulfinamide adduct. A novel nanoflow liquid chromatography/ion trap multistage mass spectrometry (nanoLC-IT/MS3) method was established to assess exposure to AαC and the tobacco-associated bladder carcinogen 4-aminobiphenyl (4-ABP) through their Hb sulfinamide adducts. Following mild acid hydrolysis of Hb in vitro, the liberated AαC and 4-ABP were derivatized with acetic anhydride to form the N-acetylated amines, which were measured by nanoLC-IT/MS3. The limits of quantification (LOQ) for AαC- and 4-ABP-Hb sulfinamide adducts were ≤7.1 pg/g Hb. In a pilot study, the mean level of Hb sulfinamide adducts of AαC and 4-ABP were, respectively, 3.4-fold and 4.8-fold higher in smokers (>20 cigarettes/day) than nonsmokers. In contrast, the major DNA adducts of 4-ABP, N-(2'-deoxyguanosin-8-yl)-4-aminobiphenyl, and AαC, N-(2'-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole, were below the LOQ (3 adducts per 109 bases) in white blood cell (WBC) DNA of smokers and nonsmokers. These findings reaffirm that tobacco smoke is a major source of exposure to AαC. Hb sulfinamide adducts are suitable biomarkers to biomonitor 4-ABP and AαC; however, neither carcinogen binds to DNA in WBC, even in heavy smokers, at levels sufficient for biomonitoring.

Cancer, culture, and health disparities: time to chart a new course?

Little progress has been made over the last 40 years to eliminate the racial/ethnic differences in incidence, morbidity, avoidable suffering, and mortality from cancer that result from factors beyond genetic differences. More effective strategies to promote equity in access and quality care are urgently needed because the changing demographics of the United States portend that this disparity will not only persist but significantly increase. Such suffering is avoidable. The authors posit that culture is a prime factor in the persistence of health disparities. However, this concept of culture is still poorly understood, inconsistently defined, and ineffectively used in practice and research. The role of culture in the causal pathway of disparities and the potential impact of culturally competent cancer care on improving cancer outcomes in ethnic minorities has, thus, been underestimated. In this article, the authors provide a comprehensive definition of culture and demonstrate how it can be used at each stage of the cancer care continuum to help reduce the unequal burden of cancer. The authors conclude with suggestions for clinical practice to eliminate the disconnection between evidence-based, quality, cancer care and its delivery to diverse population groups.

The Minnesota Green Tea Trial (MGTT), a randomized controlled trial of the efficacy of green tea extract on biomarkers of breast cancer risk: study rationale, design, methods, and participant characteristics.

PURPOSE: The Minnesota Green Tea Trial (MGTT) was a randomized, placebo-controlled, double-blinded trial investigating the effect of daily green tea extract consumption for 12 months on biomarkers of breast cancer risk. METHODS: Participants were healthy postmenopausal women at high risk of breast cancer due to dense breast tissue with differing catechol-O-methyltransferase (COMT) genotypes. The intervention was a green tea catechin extract containing 843.0 ± 44.0 mg/day epigallocatechin gallate or placebo capsules for 1 year. Annual digital screening mammograms were obtained at baseline and month 12, and fasting blood and 24-h urine samples were provided at baseline and at months 6 and 12. Primary endpoints included changes in percent mammographic density, circulating endogenous sex hormones, and insulin-like growth factor axis proteins; secondary endpoints were changes in urinary estrogens and estrogen metabolites and circulating F2-isoprostanes, a biomarker of oxidative stress. RESULTS: The MGTT screened more than 100,000 mammograms and randomized 1,075 participants based on treatment (green tea extract vs. placebo), stratified by COMT genotype activity (high COMT vs. low/intermediate COMT genotype activity). A total of 937 women successfully completed the study and 138 dropped out (overall dropout rate = 12.8 %). CONCLUSIONS: In this paper we report the rationale, design, recruitment, participant characteristics, and methods for biomarker and statistical analyses.

Fried meat intake is a risk factor for lung adenocarcinoma in a prospective cohort of Chinese men and women in Singapore.

Probable human carcinogens are generated during Chinese-style high-temperature cooking of meat and have been detected in the ambient air and on the meat surface. Although the inhalation of these compounds is an established risk factor for lung cancer, exposure via fried meat consumption has not yet been prospectively evaluated as a risk factor. The relationship between fried meat intake and lung cancer risk was investigated using data from a prospective cohort study among Chinese in Singapore. Lung cancer cases (n = 1130) were identified from 61 321 men and women, 70% of whom were lifetime never smokers. Proportional hazards regression methods were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Overall, there was no association between fried meat intake and risk of all lung cancers combined. For lung adenocarcinoma, fried meat intake had a statistically significant association with increased risk. The association between fried meat intake and risk of lung adenocarcinoma became stronger when analyses were restricted to lifetime never smokers. Compared with the lowest tertile of fried meat intake, the HRs (95% CIs) for the second and third tertiles were 1.43 (0.98, 2.08) and 1.51 (1.03, 2.22), respectively (P for trend = 0.04). The positive association was present among both men and women. There was no association between fried meat intake and risk of non-adenocarcinomas of the lung. Our prospective results for fried meat intake support consumption as an important route of exposure to compounds from Chinese-style high-temperature cooking for the development of lung adenocarcinoma.

Calcium intake is not related to breast cancer risk among Singapore Chinese women.

There is experimental evidence that calcium protects against breast cancer development. Prospective epidemiologic studies supporting a protective effect of calcium on breast cancer risk have mainly been limited to Western populations. We examined the association between calcium intake and breast cancer risk in the Singapore Chinese Health Study, a large population-based prospective cohort. Calcium intake and supplement use was assessed by in-person interviewer using a validated food frequency questionnaire. After a mean follow-up of 14.2±3.5 years, 823 cohort participants developed invasive breast cancer. Multivariate proportional hazards regression models were fitted to examine the associations between calcium intake and breast cancer risk. Vegetables were the primary food source of calcium in this study population, followed by dairy products, grains and soy foods. Calcium intake was not associated with breast cancer risk, comparing highest quartile (>345.6 mg/1,000 kcal/day) to lowest quartile (<204.5 mg/1,000 kcal/day) of intake. There was no evidence of effect modification by menopausal status, body mass index, dietary vitamin D or stage of disease at diagnosis. Our findings do not support a hypothesis for calcium in breast cancer chemoprevention, contrary to findings from previous studies among Western populations with higher calcium intake primarily from dairy products and supplements.

Sleep duration, spot urinary 6-sulfatoxymelatonin levels and risk of breast cancer among Chinese women in Singapore.

We previously reported an inverse association between sleep duration and breast cancer risk in the prospective, population-based Singapore Chinese Health Study (SCHS) cohort (Wu et al., Carcinogenesis 2008;29:1244-8). Sleep duration was significantly positively associated with 6-sulfatoxymelatonin (aMT6s) levels determined in a spot urine, but aMT6s levels in breast cancer cases were lacking (Wu et al., Carcinogenesis 2008;29:1244-8). We updated the sleep duration-breast cancer association with 14 years of follow-up of 34,028 women in the SCHS. In a nested case-control study conducted within the SCHS, randomly timed, prediagnostic urinary aMT6s concentrations were compared between 248 incident breast cancer and 743 individually matched cohort controls. Three female controls were individually matched to each case on age at baseline interview (within 3 years), dialect group, menopausal status, date of baseline interview (within 2 years), date of urine sample collection (within 6 months) and timing of urine collection during the day (within 1 hr). Cox proportional hazards and conditional regression models with appropriate adjustment for confounders were used to examine the sleep- and aMT6s-breast cancer relationships. Breast cancer risk was not significantly associated with sleep duration; adjusted odds ratio (OR) for 9+ vs. ≤ 6 hr is 0.89 [95% confidence interval (95% CI) = 0.64-1.22]. Prediagnostic aMT6s levels did not differ between breast cancer cases and matched controls; adjusted OR for highest versus lowest quartiles is 1.00 (95% CI = 0.64-1.54). We conclude that sleep duration is not significantly associated with breast cancer risk reduction. Melatonin levels derived from randomly timed spot urine are unrelated to breast cancer. Randomly timed, spot urine-derived melatonin levels are noninformative as surrogates of nocturnal melatonin production.

Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program.

BACKGROUND: Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort. METHODS: Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, apoptotic protease-activating factor 1 (Apaf-1), Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. "Smoking intensity" quantified the impact of duration and daily frequency of smoking. RESULTS: Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P < .001). Apaf-1, E-cadherin, and p53 were prognostic for outcome (P = .005, .014, and .032, respectively); E-cadherin remained prognostic following multivariable analysis (P = .040). Combined alterations in all 9 biomarkers were prognostic by univariable (P < .001) and multivariable (P = .006) analysis. A multivariable model that included all 9 biomarkers and smoking intensity had greater accuracy in predicting prognosis than models composed of standard clinicopathological covariates without or with smoking intensity (P < .001 and P = .018, respectively). CONCLUSIONS: Apaf-1, E-cadherin, and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the 9-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters alone.

Genetic polymorphisms of epidermal growth factor in relation to risk of hepatocellular carcinoma: two case-control studies.

BACKGROUND: Earlier, we reported a highly statistically significant association between T-helper 1 (Th1) and Th2 cytokine genotypes and hepatocellular carcinoma (HCC) risk among natives of southern Guangxi, China, a hyperendemic region for HCC. Epidermal growth factor (EGF) plays a critical role in malignant transformation of hepatocytes and tumor progression. A polymorphism in the EGF gene (61A > G) results in elevation of EGF in liver tissues and blood. Epidemiological data are sparse on the possible association between EGF genetic polymorphism and HCC risk. METHODS: The EGF 61A > G polymorphism, multiple Th1 and Th2 genotypes, and environmental risk factors for HCC were determined on 117 HCC cases and 225 healthy control subjects among non-Asians of Los Angeles County, California, a low-risk population for HCC, and 250 HCC cases and 245 controls of southern Guangxi, China. RESULTS: Following adjustment for all known or suspected HCC risk factors, non-Asians in Los Angeles who possessed at least one copy of the high activity 61*G allele of the EGF gene showed a statistically non-significant, 78% increased risk of HCC compared with those possessing the EGF A/A genotype. This EGF-HCC risk association significantly strengthened among heavy users of alcohol [odds ratio (OR) = 3.44, 95% confidence interval (CI) = 0.93-12.76, P = 0.065)], and among individuals carrying the high-risk Th1/Th2 genotypes for HCC (OR = 3.34, 95% CI = 1.24-9.03, P = 0.017). No association between EGF genotype and HCC risk was observed among Chinese in southern Guangxi, China. CONCLUSION: Genetic polymorphism in the EGF gene resulting in elevated level of EGF, may contribute to HCC risk among low-risk non-Asians in Los Angeles.

Smoking cessation and mortality among middle-aged and elderly Chinese in Singapore: the Singapore Chinese Health Study.

OBJECTIVE: This study determines if recent smoking cessation, compared with long-term cessation, can reduce mortality risk associated with smoking. METHODS: Data from the Singapore Chinese Health Study, a cohort study of middle-aged and elderly Chinese in Singapore, were analysed (n=48 251). Smoking status was evaluated at recruitment between 1993 and 1998 and reassessed between 1999 and 2004. Participants were classified as never-smokers, long-term quitters (quit before recruitment, mean 17.0 years), new quitters (quit between recruitment and second interview, mean 4.3 years) and current smokers. Mortality was ascertained by linkage with the nationwide death registry. RESULTS: After a mean follow-up of 8.1 years, 6003 deaths had occurred by 31 December 2009. Compared with current smokers, the adjusted HR (95% CI) for total mortality was 0.84 (0.76 to 0.94) for new quitters, 0.61 (0.56 to 0.67) for long-term quitters and 0.49 (0.46 to 0.53) for never-smokers. New quitters had 24% reduction in lung cancer mortality (HR: 0.76, 95% CI 0.57 to 1.00) and long-term quitters had 56% reduction (HR: 0.44, 95% CI 0.35 to 0.57). Risk for coronary heart disease mortality was reduced in new quitters (HR: 0.84, 95% CI 0.66 to 1.08) and long-term quitters (HR: 0.63, 95% CI 0.52 to 0.77), although the result for new quitters was of borderline significance due to relatively small number of cardiovascular deaths. Risk for chronic pulmonary disease mortality was reduced in long-term quitters but increased in new quitters. CONCLUSION: Significant reduction in risk of total mortality, specifically for lung cancer mortality, can be achieved within 5 years of smoking cessation.

DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 4-aminobiphenyl are infrequently detected in human mammary tissue by liquid chromatography/tandem mass spectrometry.

Some epidemiological investigations have revealed that frequent consumption of well-done cooked meats and tobacco smoking are risk factors for breast cancer in women. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine that is formed in well-done cooked meat, and 4-aminobiphenyl (4-ABP) is an aromatic amine that arises in tobacco smoke and occurs as a contaminant in the atmosphere. Both compounds are rodent mammary carcinogens, and putative DNA adducts of PhIP and 4-ABP have been frequently detected, by immunohistochemistry (IHC) or (32)P-post-labeling methods, in mammary tissue of USA women. Because of these findings, PhIP and 4-ABP have been implicated as causal agents of human breast cancer. However, the biomarker data are controversial: both IHC and (32)P-post-labeling are non-selective screening methods and fail to provide confirmatory spectral data. Consequently, the identities of the lesions are equivocal. We employed a specific and sensitive liquid chromatography/mass spectrometry (MS) method, to screen tumor-adjacent normal mammary tissue for DNA adducts of PhIP and 4-ABP. Only 1 of 70 biopsy samples obtained from Minneapolis, Minnesota breast cancer patients contained a PhIP-DNA adduct. The level was three adducts per 10(9) nucleotides, a level that is 100-fold lower than the mean level of PhIP adducts reported by IHC or (32)P-post-labeling methods. The occurrence of 4-ABP-DNA adducts was nil in those same breast tissues. Our findings, derived from a specific mass spectrometry method, signify that PhIP and 4-ABP are not major DNA-damaging agents in mammary tissue of USA women and raise questions about the roles of these chemicals in breast cancer.

Cytochrome P4501A2 phenotype and bladder cancer risk: The Shanghai bladder cancer study.

Cytochrome P450 1A2 (CYP1A2) is hypothesized to catalyze the activation of arylamines, known human bladder carcinogens present in cigarette smoke. The relationship between CYP1A2 phenotype and bladder cancer risk was examined in a case-control study involving 519 patients and 514 controls in Shanghai, China. Both CYP1A2 and N-acetyltransferase 2 (NAT2) phenotypic status were determined by a caffeine-based urinary assay. Our study showed that among smokers at urine collection, patients with bladder cancer had statistically significantly higher CYP1A2 phenotype scores compared to control subjects (p = 0.001). The odds ratios (95% confidence intervals) of bladder cancer for the second, third and fourth quartiles of the CYP1A2 score were 1.31 (0.53-3.28), 2.04 (0.90-4.60) and 2.82 (1.32-6.05), respectively, relative to the lowest quartile (p for trend = 0.003). NAT2 slow acetylation phenotype was associated with a statistically significant 40% increased risk of bladder cancer, and the relationship was independent of subjects' smoking status. Subjects possessing the NAT2 slow acetylation phenotype and the highest tertile of CYP1A2 scores showed the highest risk for bladder cancer. Their odds ratios (95% confidence intervals) was 2.13 (1.24-3.68) relative to their counterparts possessing the NAT2 rapid acetylation phenotype and the lowest tertile of CYP1A2 scores. The findings of our study demonstrate that CYP1A2 phenotype may be an important contributing factor in the development of smoking-related bladder cancer in humans.

Green and black tea intake in relation to prostate cancer risk among Singapore Chinese.

PURPOSE: Tea is one of the most commonly consumed beverages worldwide. To date, observational data from prospective cohort studies investigating the relationship between green and black tea intake and prostate cancer risk are sparse and equivocal. In a population-based, prospective cohort study of Chinese men in Singapore, we investigated the relationship between green and black tea intake and prostate cancer risk. METHODS: Tea consumption data for 27,293 men were collected at baseline (between 1993 and 1998) using a validated food frequency questionnaire. After an average of 11.2 years of follow-up, 298 men had developed prostate cancer. Proportional hazards regression methods were used to assess the associations between tea intake and prostate cancer risk. RESULTS: There was no association between daily green tea intake and prostate cancer risk, compared with no green tea intake [hazard ratio (HR) = 1.08; 95 % confidence interval (CI) 0.79, 1.47]. For black tea, a statistically significant positive association and trend were observed for daily intake compared with no black tea intake (HR = 1.41, 95 % CI 1.03, 1.92; p for trend <0.01) CONCLUSIONS: Few prospective data are available from populations that have both a high level and wide range of black and green tea intake; this study represents a unique opportunity to evaluate their individual effects on prostate cancer risk. Our findings support the notion that green tea intake does not protect against prostate cancer and that black tea intake may increase prostate cancer risk.

Mortality due to coronary heart disease and kidney disease among middle-aged and elderly men and women with gout in the Singapore Chinese Health Study.

OBJECTIVES: Whether the link between gout and mortality is causal or confounded by lifestyle factors or comorbidities remains unclear. Studies in Asia are warranted due to the rapid modernisation of the locale and ageing of the population. METHODS: The association between gout and mortality was examined in a prospective cohort, the Singapore Chinese Health Study, comprising 63 257 Singapore Chinese individuals, aged 45-74 years during the enrolment period of 1993-8. All enrollees were interviewed in person on lifestyle factors, current diet and medical histories. All surviving cohort members were contacted by telephone during 1999-2004 to update selected exposure and medical histories (follow-up I interview), including the history of physician-diagnosed gout. Cause-specific mortality in the cohort was identified via record linkage with the nationwide death registry, up to 31 December 2009. RESULTS: Out of 52 322 participants in the follow-up I interview, 2117 (4.1%) self-reported a history of physician-diagnosed gout, with a mean age at diagnosis of 54.7 years. After a mean follow-up period of 8.1 years, there were 6660 deaths. Relative to non-gout subjects, subjects with gout had a higher risk of death (HR 1.18; 95% CI 1.06 to 1.32), and specifically from death due to coronary heart disease (CHD) (HR 1.38, 95% CI 1.10 to 1.73) and kidney disease (HR 5.81, 95% CI 3.61 to 9.37). All gout-mortality risk associations were present in both genders but the risk estimates appeared higher for women. CONCLUSION: Gout is an independent risk factor for mortality, and specifically for death due to CHD and kidney disease.

Soy intake and risk of type 2 diabetes in Chinese Singaporeans [corrected].

PURPOSE: To examine the association between soy products and their components, isoflavones and protein, and incident type 2 diabetes in a population with varied soy intake and high rates of diabetes. METHODS: We used data from the Singapore Chinese Health Study, including 43,176 Chinese men and women aged 45-74 years, free of chronic disease at baseline (1993-1998) and followed through 2004. Intake of individual soy items, total unsweetened soy, and soy components was assessed by food-frequency questionnaire and examined with type 2 diabetes risk using Cox regression. RESULTS: During an average follow-up of 5.7 years, 2,252 of the 43,176 participants included in the current analyses developed diabetes. After adjustment for potential confounders and BMI, consumption of unsweetened soy was inversely associated with diabetes risk. Hazard ratios (HRs) and 95% CI for diabetes across unsweetened soy intake categories (none, 1-4/month, 1-2/week, 3-4/week, ≥ 5/week) were: 1 (referent), 0.81 (0.67-0.97), 0.76 (0.63-0.91), 0.76 (0.63-0.92), and 0.72 (0.59-0.89), respectively (P (trend) = 0.015). Conversely, in multivariate models, consuming sweetened soybean drink was positively associated with diabetes risk. HRs for diabetes across soybean drink intake categories (none, 1-3/month, 1/week, ≥ 2/week) were: 1 (referent), 1.07 (0.95-1.20), 1.12 (1.00-1.26), and 1.13 (1.00-1.28), respectively (P (trend) = 0.03). Furthermore, after full adjustment, including adjustment for sweetened soy items, we observed a marginally significant inverse association between isoflavone intake and diabetes (HR for the fifth compared to the first quintile: 0.76; 95% CI: 0.58-1.00; P (trend) = 0.08). CONCLUSIONS: The current findings support a protective role for unsweetened soy foods and isoflavones on risk of type 2 diabetes.

Histological versus clinical cirrhosis in chronic hepatitis C: does race/ethnicity really matter?

UNLABELLED: Liver fibrosis progression in hepatitis C virus (HCV) infection has been in part associated with race/ethnicity. Little is known of the frequency of clinical cirrhosis in Asian patients in the US. AIM: To compare histological and clinical features of chronic hepatitis C (CHC) in a multiethnic cohort of patients. METHODS: Retrospective query of an electronic medical registry for CHC patients evaluated from 1999 to 2005. Histological cirrhosis was defined as advanced METAVIR fibrosis score at biopsy. Clinical cirrhosis was defined as any of: varices, ascites, or splenomegaly. Liver cirrhosis was defined as either histological or clinical cirrhosis. Chi-square tests, t tests, and logistic regression method were used for data analysis. RESULTS: Six hundred and ninety-two patients were categorized into four racial-ethnic groups: 292 Caucasian (C), 145 Hispanic (H), 121 African American (AA), and 134 Asian (As) patients. Median age of AA (54 years) and As (53) was higher than C (52), or H (50) (p < 0.05). H patients had a higher percentage of alcohol abuse (60%) than AA and C (42-44%) and As (14%; p < 0.0001). Body mass index (BMI) was significantly lower in Asians compared to all other groups (p < 0.0001). Features of the metabolic syndrome were common, ranging from 28% in As to 72% in H patients. Liver cirrhosis was found in 53% H, 35% C, 29% As, and 19% AA. In multivariable analysis, only alcohol abuse, BMI, diabetes mellitus (DM), and age were significantly associated with liver cirrhosis. There was a trend for AA to have less cirrhosis, either histological or clinical (p = 0.08). CONCLUSIONS: Using only histology, liver cirrhosis was significantly underestimated. In our cohort, severity of CHC was not clearly affected by race when alcohol use and features of the metabolic syndrome were taken into consideration. However, there was a trend for African Americans to have lower cirrhosis rates.

Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore.

Cigarette smoking is a risk factor for colorectal cancer. Putative colorectal procarcinogens in tobacco smoke include polycyclic aromatic hydrocarbons and heterocyclic aromatic amines that are known substrates of glutathione S-transferases (GSTs). This study examined the influence of functional GST gene polymorphisms on the smoking-colorectal cancer association in a population known to be minimally exposed to dietary sources of these procarcinogens. Incident cases of colorectal cancer (n = 480) and matched controls (n = 1167) were selected from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women who have been followed since 1993. We determined the deletion polymorphisms of GSTM1 and GSTT1 and the functional polymorphism at codon 105 of GSTP1 for each subject. A three level composite GST index was used to examine if GST profile affected a smoker's risk of developing colorectal cancer. While there was no statistically significant association between cigarette smoking and colorectal cancer risk among subjects absent of any at-risk GST genotypes, smokers possessing two to three at-risk GST genotypes exhibited a statistically significant increased risk of colorectal cancer compared with non-smokers (P = 0.0002). In this latter stratum, heavy smokers exhibited a >5-fold increased risk relative to never-smokers (odds ratio, 5.43; 95% confidence interval, 2.22-13.23). Subjects with one at-risk GST genotype displayed a statistically significant but weaker association with smoking. These findings suggest that GST gene polymorphisms influence interindividual susceptibility to smoking-associated colorectal cancer. Our data indicate an important role for GST enzymes in the detoxification of colorectal carcinogens in tobacco smoke.

Body mass index and risk of colorectal cancer in Chinese Singaporeans: the Singapore Chinese Health Study.

BACKGROUND: The authors chose to examine the association between body mass index (BMI) and incident colorectal cancer across the spectrum of BMI, including underweight persons, because detailed prospective cohort data on this topic in Asians is scarce, as is data on underweight persons (BMI, <18.5 kg/m(2)) in any population. METHODS: Analysis of the Singapore Chinese Health Study included 51,251 men and women aged 45-74 years enrolled in 1993-1998 and followed through 2007. Incident cancer cases and deaths among cohort members were identified through record linkage, and 980 cases were identified. Cox regression models were used to investigate the association of baseline BMI with risk of incident colorectal cancer during a mean of 11.5 years of follow-up. RESULTS: A significant, U-shaped, quadratic association was observed between BMI and colon cancer risk, with increased risk in BMIs ≥27.5 and <18.5 kg/m(2). The association was more pronounced in never smokers and most prominent when further limiting the sample to those free of diabetes and cases with longer than 5 years of follow-up. Localized cases had a more pronounced association in BMIs ≥27.5, whereas advanced cases had a more pronounced association in BMIs <18.5 kg/m(2) . No association was found in relation to rectal cancer risk. The association was also stronger among patients aged 65 years and older. CONCLUSIONS: BMI displays a U-shaped, quadratic association with colon cancer risk in this Chinese population in Southeast Asia.

Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis-related hepatocellular carcinoma.

BACKGROUND: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6. METHODS: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County. RESULTS: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18-4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele. CONCLUSIONS: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC.

Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore.

The MDM2 oncoprotein regulates the p53 pathway and, while functional polymorphisms of the MDM2 and p53 genes have been investigated for association with breast cancer risk, results are largely null or non-conclusive. We have earlier reported that the increased intake of soy isoflavones reduces risk of postmenopausal breast cancer, and experimental studies suggest that dietary isoflavones can down-regulate the expression of the MDM2 oncoprotein. In this study, we investigated the association between the MDM2 SNP309 and TP53 R72P polymorphisms and breast cancer risk using a case-control study of 403 cases and 662 controls nested among 35,303 women in The Singapore Chinese Health Study, a population-based, prospective cohort of middle-aged and elderly men and women who have been continuously followed since 1993. The G allele of the TP53 R72P polymorphism and T allele of the MDM2 SNP309 polymorphism were putative high-risk alleles and exhibited a combined gene-dose-dependent joint effect on breast cancer risk that was more clearly observed in postmenopausal women. Among postmenopausal women, the simultaneous presence of G allele in TP53 and T allele in MDM2 polymorphisms was associated with an odds ratio (OR) of 2.42 [95% confidence interval (CI) 1.06-5.50]. Furthermore, the protective effect of dietary soy isoflavones on postmenopausal breast cancer was mainly confined to women homozygous for the high activity MDM2 allele (GG genotype). In this genetic subgroup, women consuming levels of soy isoflavones above the median level exhibited risk that was half of those with below median intake (OR 0.52; 95% CI 0.28-0.99). Our findings support experimental data implicating combined effects of MDM2 protein and the p53-mediated pathway in breast carcinogenesis, and suggest that soy isoflavones may exert protective effect via down-regulation of the MDM2 protein.