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The article investigates the effects of soy and green tea consumption on mammographic density, a biomarker for breast cancer risk, among Chinese women in Singapore. According to the authors, findings suggest that both regular green tea consumption and high soy intake may have beneficial effects on the breast. The authors add that the effect of green tea on percent mammographic density (PMD) may be stronger than the effect of soy.

Purpose: Antibodies to select Epstein-Barr virus (EBV) proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against EBV nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years pre-diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay., Design: Mammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using pre-diagnostic NPC sera from two independent cohorts in Singapore and Shanghai, P.R. China., Results: At 95% sensitivity, 487V yielded a 94.9% specificity compared to 86.1% for 487A. EBNA1 deleted for the conserved glycine-alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390-641) showed lower specificity (84.8%) than the EBNA1 GAr deleted construct (92.4%) at 95% sensitivity., Conclusion: Although EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr but with residues consistently detected in Southeast Asian NPC tumors is optimal for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection.

Limited data are reported on the association between low-carbohydrate diet (LCD) score, a comprehensive measure of dietary pattern according to sources of carbohydrate, fat, and protein, and risk of hepatocellular carcinoma (HCC). We evaluated this score with HCC risk in the Singapore Chinese Health Study, a prospective cohort of 63,275 middle-aged and elderly Chinese living in Singapore and recruited during 1993-1998 period. LCD scores were derived from the semi-quantitative food frequency questionnaire at baseline. A nested case-control study involved 197 HCC cases and 465 controls was also constructed among 28,346 participants who provided blood samples. Cox proportional hazard regression method was used to calculate HRs and 95% confidence intervals (CI) for HCC with different levels of LCD scores. Conditional logistic regression was performed for the case-control study analysis. After 17.6 years of follow-up with 819,573 person-years, 561 participants developed primary HCC. Although there was a null association between total LCD score and HCC risk (HRper-SD increment = 1.07; 95% CI, 0.98-1.16; Ptrend = 0.06), there was a positive association between animal-based LCD and the risk of HCC (HRper-SD increment = 1.11; 95% CI, 1.02-1.21; Ptrend = 0.01). Furthermore, this association was present in both HBsAg-negative and HBsAg-positive individuals in the case-control study. In stratified analysis for the entire cohort, this positive association was only present in those who consumed alcoholic beverages monthly or less frequent but not in weekly or daily drinker (Pinteraction = 0.79). In summary, a diet with lower carbohydrate, higher animal fat and protein was significantly associated with higher risk of HCC among Chinese Singaporeans., Prevention Relevance: In a large cohort study of more than 63,000 Chinese Singaporeans, we found that a diet with lower carbohydrate and higher animal fat and protein was associated with increased risk of HCC, suggesting that dietary modification could be an effective strategy in primary prevention to reduce the HCC burden., (©2024 American Association for Cancer Research.)

Background: Colorectal cancer is common cancer with a high mortality rate. Low-carbohydrate diet (LCD) score holistically evaluates the LCD pattern from carbohydrate, protein, and fat intake. Epidemiologic data of LCD-colorectal cancer association are sparse., Methods: We evaluated the associations between LCD (i.e., total, animal- and plant-based) and colorectal cancer risk in the Singapore Chinese Health Study, a population-based prospective cohort study including 61,321 Chinese in Singapore who were 45 to 74 years old at baseline. Cox proportional hazard regression model was used to determine the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with LCD after adjusting for potential confounders, including age, sex, BMI, physical activity, family history of colorectal cancer, etc., Results: After an average of 19.5 years of follow-up, 2,520 participants developed colorectal cancer (1,608 colon cancer and 912 rectal cancer). Overall, the association between total or plant-based LCD scores with the risk of colorectal, colon, or rectal cancer was null (all Ptrend ≥ 0.28). The animal-based LCD was modestly associated with colon cancer risk (Ptrend = 0.02), but not with rectal cancer. Compared with the lowest quartile, HRs (95% CIs) of colon cancer for quartiles 2, 3, and 4 of animal-based LCD were 1.12 (0.98-1.29), 1.27 (1.10-1.46), and 1.14 (0.99-1.31), respectively., Conclusions: A low-level carbohydrate diet with a high level of animal protein and fat was associated with a moderate increase in the risk of colon cancer among Chinese Singaporeans., Impact: High consumption of animal protein/fat and low consumption of carbohydrates may increase colon cancer risk., (©2023 American Association for Cancer Research.)

Background: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3'-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels., Methods: Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data., Results: Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N'-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N'-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N'-oxide, and CYP2B6 genotype and levels of nicotine-N'-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid., Conclusions: These data suggest that several pathways are important in nicotine metabolism., Impact: Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation., (©2022 The Authors; Published by the American Association for Cancer Research.)

Dietary fiber or non-starch polysaccharides (NSP) may provide protection from CRC development. Epidemiologic studies on the association between dietary fiber and CRC is inconsistent are limited on NSP as a modifiable risk factor. Using the Singapore Chinese Health Study, a population-based prospective cohort of 61,321 cancer-free middle-aged or older Chinese Singaporeans, we examined the association between dietary fiber and NSP intakes and CRC risk. Fiber and NSP intakes at baseline were obtained using a validated semi-quantitative food frequency questionnaire coupled with the Singapore Food Composition Database. Cox proportional hazard regression model was used to estimate the hazard ratios (HRs) and respective 95% confidence intervals (CIs) for CRC associated with dietary fiber and NSP intakes after adjusting for potential confounders. After an average of 17.5 years of follow-up, 2,140 participants developed CRC. NSP was inversely associated with the risk of CRC in a dose-dependent manner whereas dietary fiber was not associated with risk of CRC overall or histologic subtypes. The multivariable-adjusted HRs (95% CIs) of CRC for quartiles 2, 3 and 4 of dietary NSP intake were 0.99 (0.88-1.11), 0.98 (0.87-1.11) and 0.84 (0.73-0.95), respectively, compared with the lowest quartile ( P trend =0.006). This inverse association was more apparent for colon cancer (HR Q4 vs. Q1 =0.79, 95% CI: 0.67-0.93, P trend =0.003) than rectal cancer (HR Q4 vs. Q1 =0.92, 95% CI: 0.74-1.13, P trend =0.53). Our findings suggested that dietary NSP but not fiber is associated with a reduced risk of colon cancer in Chinese Singaporeans., Significance: Non-starch polysaccharides may be beneficial for colorectal cancer primary prevention., Competing Interests: Conflict of Interest No conflict of interest was declared by any authors.

While the associations between individual lifestyle factors and risk of pancreatic cancer were studied extensively, their combined impact has not been examined. We evaluated the association of a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity with pancreatic cancer risk in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese aged 45 to 74 years at enrollment in 1993 to 1998 with up to 25 years of follow up. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI) with adjustment for multiple potential confounders. We identified 316 incident pancreatic cancer cases among the cohort participants after a mean 17 years of follow up. Individuals with higher composite scores representing healthier lifestyle were at significantly lower risk of pancreatic cancer. The multivariate-adjusted HRs (95% CIs) of pancreatic cancer incidence for the composite scores 2, 3, 4, 5, 6 to 7 were 0.60 (0.50-0.91), 0.48 (0.32-0.71), 0.45 (0.31-0.67), 0.41 (0.27-0.62), and 0.38 (0.24-0.62), respectively, compared with the scores 0 to 1 ( P trend < 0.0001). The inverse association was more apparent among participants without diabetes history and was robust in men and women as well as in alcohol drinkers and nondrinkers. In summary, the association for pancreatic cancer risk was stronger for the aggregated than individual healthy lifestyle factors. These findings suggest that a more comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor. PREVENTION RELEVANCE: In this large prospective Asian study, we calculated a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity and found this composite score was associated with a significant reduction in pancreatic cancer risk, by as much as 62%. This finding suggests that public health programs emphasizing comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor., (©2021 American Association for Cancer Research.)

Background: Nonalcoholic fatty liver disease (NAFLD) has become a major contributor to the rising incidence of hepatocellular carcinoma (HCC) in the United States and other developed countries. Iron, an essential metal primarily stored in hepatocytes, may play a role in the development of NAFLD-related HCC. Epidemiologic data on iron overload without hemochromatosis in relation to HCC are sparse. This study aimed to examine the associations between serum biomarkers of iron and the risk of HCC in patients with NAFLD., Methods: We identified 18,569 patients with NAFLD using the University of Pittsburgh Medical Center electronic health records from 2004 through 2018. After an average 4.34 years of follow-up, 244 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of HCC incidence associated with elevated levels of iron biomarkers with adjustment for age, sex, race, body mass index, history of diabetes, and tobacco smoking., Results: The HRs (95% CIs) of HCC for clinically defined elevation of serum iron and transferrin saturation were 2.91 (1.34-6.30) and 2.02 (1.22-3.32), respectively, compared with their respective normal range. No statistically significant association was observed for total iron-binding capacity or serum ferritin with HCC risk., Conclusions: Elevated levels of serum iron and transferrin saturation were significantly associated with increased risk of HCC among patients with NAFLD without hemochromatosis or other major underlying causes of chronic liver diseases., Impact: Clinical surveillance of serum iron level may be a potential strategy to identify patients with NAFLD who are at high risk for HCC., (©2021 American Association for Cancer Research.)

Background: Limited research has been conducted on the effect of quality diet index (QDI), which represents a comprehensive assessment of healthy diet quality and quantity, on pancreatic cancer risk in Asian populations., Methods: Using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged or older Chinese men and women, four QDI scores: the Alternative Health Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), and the Heathy Diet Indicator (HDI), at baseline were calculated. After 25 years of follow-up, 311 cohort participants developed pancreatic cancer. Cox proportional hazard regression method was used to estimate HR and 95% confidence interval (CI) for pancreatic cancer associated with higher QDI scores., Results: Higher scores of AHEI-2010, aMED, and DASH were significantly associated with lower pancreatic cancer risk (all P trend < 0.05). Compared with the lowest quartile, HRs (95% CIs) of pancreatic cancer for the highest quartiles of AHEI-2010, aMED, and DASH scores were 0.65 (0.46-0.90), 0.57 (0.38-0.85), and 0.66 (0.46-0.95), respectively. These associations were more apparent among men. Overall, there was no statistically significant difference in the QDI-pancreatic cancer risk association between subgroups stratified by levels of body mass index, history of diabetes, and smoking status., Conclusions: Higher QDI scores were significantly associated with reduced risk of pancreatic cancer., Impact: The consistent results across multiple QDIs shows that adherence to a healthy diet may lower pancreatic cancer risk, suggesting that dietary modification may be a promising approach for primary prevention of pancreatic cancer., (©2021 American Association for Cancer Research.)

Background: IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma., Methods: Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma., Results: The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both P trend <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg., Conclusions: Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development., Impact: IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development., (©2020 American Association for Cancer Research.)

Background: While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) have been described previously, their combined impact on HCC risk is unknown., Methods: The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean diet, and sleep duration, and HCC risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese men and women. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI). Conditional logistic regression method was used to evaluate this composite lifestyle score-HCC risk association among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg) and anti-hepatitis C antibody., Results: After a mean follow-up of 17.7 years, 561 participants developed HCC. Individuals with higher composite scores representing healthier lifestyles (range 0-8) were at significantly lower risk of HCC. Compared with the lowest composite score category (0-4), the HRs (95% CIs) for the composite scores of 5, 6, 7, and 8 were 0.67 (0.62-0.85), 0.61 (0.48-0.77), 0.49 (0.37-0.65), and 0.13 (0.06-0.30), respectively ( P trend < 0.0001). A similar inverse association was observed in participants with negative HBsAg and anti-hepatitis C virus (HCV)-negative serology (HR, 0.38; 95% CI, 0.19-0.79; for the highest vs. the lowest category of the composite scores; P trend = 0.001)., Conclusions: Healthy lifestyles protect against HCC development, especially for individuals without hepatitis B virus and HCV infections., Impact: This study highlights the importance of a comprehensive lifestyle modification strategy for HCC primary prevention., (©2020 American Association for Cancer Research.)

Background: Intake of tomato and/or lycopene has been associated with reduced risk of several cancers, but there is no report on the association with risk of hepatocellular carcinoma (HCC)., Methods: The associations of tomato and lycopene consumption with risk of HCC were examined in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese ages 45 to 74 years at enrollment. Diet was assessed using a validated semiquantitative food frequency questionnaire. Cox proportional hazard regression models were used to estimate HR and its 95% confidence interval (CI) of HCC with the consumption of tomato and lycopene among all cohort participants, and unconditional logistic regression was used to assess the association by hepatitis B surface antigen (HBsAg) positivity in a nested case-control study., Results: After a mean follow-up of 17.6 years, 561 incident HCC cases were identified. Higher tomato intake was associated with lower risk of HCC after adjustment for potential confounders ( P trend < 0.001). Compared with the lowest quartile, HRs (95% CIs) of HCC for the second, third, and fourth quartile of tomato intake were 0.70 (0.56-0.88), 0.73 (0.58-0.92), and 0.63 (0.49-0.81). Among HBsAg-negative individuals, the inverse association remained ( P trend = 0.03). There was no association between lycopene intake and HCC risk ( P trend = 0.54)., Conclusions: Tomato intake may offer protection against the development of HCC, particularly among individuals without chronic infection with hepatitis B virus., Impact: Tomato intake is a low-cost preventative measure against HCC that may help reduce risk due to increasing rates of nonalcoholic fatty liver disease., (©2020 American Association for Cancer Research.)

Background: Cotinine is a metabolite of nicotine. Serum and urinary cotinine are validated biomarkers for cigarette exposure. Their performance for lung cancer risk prediction has not been simultaneously examined in epidemiologic studies., Methods: A nested case-control study, including 452 incident lung cancer cases and 452 smoking-matched controls in the Shanghai cohort study, was conducted. Mass spectrometry-based methods were used to quantify cotinine in serum and urine samples collected from current smokers at baseline, on average 10 years before cancer diagnosis of cases. Logistic regression was used to estimate ORs, 95% confidence intervals (CI), and AUC ROC for lung cancer associated with higher levels of cotinine., Results: Serum and urinary cotinine levels were significantly higher in lung cancer cases than controls. Compared with the lowest quartile serum cotinine (≤0.40 nmol/mL), the OR of lung cancer for smokers in the highest quartiles (>1.39 nmol/mL) was 5.46 (95% CI, 3.38-8.81). Similarly, the OR was 5.49 (95% CI, 3.39-8.87) for highest (>16.38 nmol/mg creatinine) relative to the lowest quartile of urinary total cotinine (≤4.11 nmol/mg creatinine). A risk prediction model yielded an AUC of 0.72 (95% CI, 0.69-0.75) for serum cotinine and 0.72 (95% CI, 0.69-0.75) for urinary total cotinine combined with smoking history., Conclusions: Urinary and serum cotinine have the same performance in prediction of lung cancer risk for current smokers., Impact: Urinary cotinine is a noninvasive biomarker that can replace serum cotinine in risk prediction of future lung cancer risk for current smokers., (©2019 American Association for Cancer Research.)

2-Phenethyl isothiocyanate (PEITC) is a natural product found as a conjugate in cruciferous vegetables. It has been reported to have preventative properties against lung cancer and to inhibit metabolic activation of tobacco carcinogens. In this study, we evaluated the ability of PEITC to influence the metabolism of the human carcinogen 1,3-butadiene in current smokers in a phase II clinical trial with a crossover design. Urinary mercapturic acids of 1,3-butadiene were quantified at baseline and during PEITC treatment. Seventy-nine smokers were randomly assigned to one of two arms: PEITC followed by placebo or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Oral ingestion of PEITC increased urinary levels of BD-mercapturic acids (MHBMA and DHBMA) by 11.1% and 3.7%, respectively, but these increases were not statistically significant ( P = 0.17 and 0.64, respectively). A much stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1 : in these individuals, PEITC increased urinary levels of MHBMA by 58.7% ( P = 0.004) and 90.0% ( P = 0.001), respectively, but did not have a significant effect on urinary DHBMA. These results reveal a potentially protective effect of PEITC treatment with respect to the detoxification of 1,3-butadiene in cigarette smokers, specifically in those null for GSTT1 , and provide further evidence in support of stronger chemopreventive effects from consumption of dietary isothiocyanates in these individuals., (©2019 American Association for Cancer Research.)

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m 2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases., (©2019 American Association for Cancer Research.)

Background: The major mode of metabolism of nicotine is by hydroxylation via cytochrome P450 (CYP) 2A6, but it can also undergo glucuronidation by UDP-glucuronosyltransferases and oxidation by flavin monooxygenases (FMO). The goal of this study was to examine the potential importance of FMOs in nicotine metabolism and assess the potential impact of missense polymorphisms in active FMOs on nicotine- N '-oxide (NOX) formation., Methods: Urine samples from 106 current Chinese smokers were analyzed for nicotine metabolites by mass spectrometry. Wild-type FMO s 1-5 and their most prevalent nonsynonymous variants were cloned and overexpressed in HEK293 cells, and were tested in oxidation reactions against nicotine., Results: A strong inverse correlation was observed between the ratio of urinary 3'-hydroxycotinine/cotinine, a measure of CYP2A6 activity, and the urinary levels of NOX alone ( r = -0.383; P < 0.001) or NOX measured as a ratio of total nicotine metabolites ( r = -0.414; P < 0.001) in smokers. In addition to FMO1 and FMO3, the functional FMO2 427Q isoform was active against nicotine, whereas FMO4 and FMO5 exhibited low activity against nicotine ( K m > 5.0 mmol/L). Significant ( P < 0.05) decreases in N '-oxidation activity ( V max / K m ) were observed for the FMO1 I303V , FMO3 N61S , FMO3 D132H , FMO3 V257M , and FMO3 E308G variants in vitro when compared with their respective wild-type isoforms; the truncated FMO2 Q472stop isoform exhibited no enzyme activity., Conclusions: These data indicate that increases in nicotine- N '-oxidation occur in subjects with deficient CYP2A6 activity, and that several FMO enzymes are active in nicotine- N '-oxidation., Impact: Several common missense FMO variants are associated with altered enzyme activity against nicotine and may play an important role in nicotine metabolism in low-CYP2A6 activity subjects., (©2018 American Association for Cancer Research.)

Epidemiologic and animal studies suggest a protective role of green tea against breast cancer. However, the underlying mechanism is not understood. We conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density (MD), as a potential mechanism, involving 1,075 healthy postmenopausal women. Women assigned to the treatment arm consumed daily 4 decaffeinated GTE capsules containing 1,315 mg total catechins, including 843 mg epigallocatechin-3-gallate (EGCG) for 12 months. A computer-assisted method (Madena) was used to assess MD in digital mammograms at baseline and month 12 time points in 932 completers (462 in GTE and 470 in placebo). GTE supplementation for 12 months did not significantly change percent MD (PMD) or absolute MD in all women. In younger women (50-55 years), GTE supplementation significantly reduced PMD by 4.40% as compared with the placebo with a 1.02% PMD increase from pre- to postintervention ( P = 0.05), but had no effect in older women ( P interaction = 0.07). GTE supplementation did not induce MD change in other subgroups of women stratified by catechol- O -methyltransferase genotype or level of body mass index. In conclusion, 1-year supplementation with a high dose of EGCG did not have a significant effect on MD measures in all women, but reduced PMD in younger women, an age-dependent effect similar to those of tamoxifen. Further investigation of the potential chemopreventive effect of green tea intake on breast cancer risk in younger women is warranted. Cancer Prev Res; 10(12); 710-8. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Liver injury effects of green tea-based products have been reported in sporadic case reports. However, no study has examined systematically such adverse effects in an unbiased manner. We examined the potential effects of a high, sustained oral dose of green tea extract (GTE) on liver injury measures in a randomized, placebo-controlled, double-blinded phase II clinical trial, which enrolled 1,075 women with the original aim to assess the effect of daily GTE consumption for 12 months on biomarkers of breast cancer risk. The current analysis examined the effect of GTE consumption on liver injury in 1,021 participants (513 in GTE and 508 in placebo arm) with normal baseline levels of liver enzymes. Among women in the GTE arm, alanine aminotransferase (ALT) increased by 5.4 U/L [95% confidence interval (CI), 3.6-7.1] and aspartate aminotransferase increased by 3.8 U/L (95% CI, 2.5-5.1), which were significantly higher than those among women in the placebo arm (both P < 0.001). Overall, 26 (5.1%) women in GTE developed moderate or more severe abnormalities in any liver function measure during the intervention period, yielding an OR of 7.0 (95% CI, 2.4-20.3) for developing liver function abnormalities as compared with those in the placebo arm. ALT returned to normal after dechallenge and increased again after one or more rechallenges with GTE. The rise-fall pattern of liver enzyme values following the challenge-dechallenge cycles of GTE consumption strongly implicates the effect of high-dose GTE on liver enzyme elevations. Cancer Prev Res; 10(10); 571-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Cigarette smoke contains relatively large quantities of volatile organic toxicants or carcinogens such as benzene, acrolein, and crotonaldehyde. Among their detoxification products are mercapturic acids formed from glutathione conjugation, catalyzed in part by glutathione S-transferases (GST). A randomized phase II clinical trial with a crossover design was conducted to evaluate the effect of 2-phenethyl isothiocyanate (PEITC), a natural product formed from gluconasturtiin in certain cruciferous vegetables, on the detoxification of benzene, acrolein, and crotonaldehyde in 82 cigarette smokers. Urinary mercapturic acids of benzene, acrolein, and crotonaldehyde at baseline and during treatment were quantified. Overall, oral PEITC supplementation increased the mercapturic acid formed from benzene by 24.6% (P = 0.002) and acrolein by 15.1% (P = 0.005), but had no effect on crotonaldehyde. A remarkably stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals, PEITC increased the detoxification metabolite of benzene by 95.4% (P < 0.001), of acrolein by 32.7% (P = 0.034), and of crotonaldehyde by 29.8% (P = 0.006). In contrast, PEITC had no effect on these mercapturic acids in smokers possessing both genes. PEITC had no effect on the urinary oxidative stress biomarker 8-iso-prostaglandin F2α or the inflammation biomarker prostaglandin E2 metabolite. This trial demonstrates an important role of PEITC in detoxification of environmental carcinogens and toxicants which also occur in cigarette smoke. The selective effect of PEITC on detoxification in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiologic findings of stronger protection by dietary isothiocyanates against the development of lung cancer in such individuals. Cancer Prev Res; 9(7); 598-606. ©2016 AACR., (©2016 American Association for Cancer Research.)

2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in watercress and other cruciferous vegetables, is an inhibitor of the metabolic activation and lung carcinogenicity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in F344 rats and A/J mice. We carried out a clinical trial to determine whether PEITC also inhibits the metabolic activation of NNK in smokers. Cigarette smokers were recruited and asked to smoke cigarettes containing deuterium-labeled [pyridine-D4]NNK for an acclimation period of at least 1 week. Then subjects were randomly assigned to one of two arms: PEITC followed by placebo, or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. The NNK metabolic activation ratio [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL was measured in urine samples to test the hypothesis that PEITC treatment modified NNK metabolism. Eighty-two smokers completed the study and were included in the analysis. Overall, the NNK metabolic activation ratio was reduced by 7.7% with PEITC treatment (P = 0.023). The results of this trial, while modest in effect size, provide a basis for further investigation of PEITC as an inhibitor of lung carcinogenesis by NNK in smokers. Cancer Prev Res; 9(5); 396-405. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Nutrients involved in one-carbon metabolism are hypothesized to protect against pancreatic cancer development., Methods: The Singapore Chinese Health Study database was used to prospectively examine the association between intake of one-carbon metabolism-related nutrients and pancreatic cancer risk. Between 1993 and 1998, 63,257 men and women ages 45 to 74 years were enrolled into the cohort. The daily intakes of the following one-carbon metabolism-related nutrients were assessed at enrollment using a 165-item food frequency questionnaire: betaine, choline, folate, and vitamins B2, B6, and B12. Multivariable HRs and 95% confidence intervals (CI) for pancreatic cancer risk associated with dietary intakes of one-carbon metabolism-related nutrients were calculated., Results: As of December 2013, 271 incident pancreatic cancer cases were identified during an average of 16.3 years of follow-up. Higher intakes of vitamin B6 and choline were associated with statistically significant decreases in the risk of developing pancreatic cancer. Compared with the lowest quartile, HRs (95% CIs) for the highest quartiles of vitamin B6 and choline were 0.52 (0.36-0.74; P trend = 0.001) and 0.67 (0.48-0.93; P trend = 0.04), respectively. There were no clear associations between the other one-carbon metabolism-related nutrients and pancreatic cancer risk., Conclusion: Our study suggests that higher intake of vitamin B6 and choline may lower the risk of pancreatic cancer., Impact: Our prospective findings are consistent with the in vivo evidence for protective roles of vitamin B6 and choline on pancreatic cancer development., (©2015 American Association for Cancer Research.)

Background: Despite experimental evidence showing chemopreventive effects of coffee-related compounds on gastric carcinogenesis, epidemiologic studies generally do not support coffee-gastric cancer associations. Observational data are lacking among high-risk populations with sufficient regular coffee consumption., Methods: We examined the association between caffeinated coffee intake and gastric cancer risk in a population-based cohort that enrolled 63,257 Chinese men and women ages 45 to 74 years between 1993 and 1998 in Singapore. Incident gastric cancer cases (n = 647) were identified after a mean follow-up of 14.7 years. Biomarkers of Helicobacter pylori (H. pylori) infection were measured in a subset of gastric cancer cases with blood collected before cancer diagnosis and their matched controls., Results: In the total cohort, daily versus nondaily coffee intake was associated with a statistically nonsignificant decrease in gastric cancer risk [HR = 0.85; 95% confidence interval (CI), 0.69-1.04]. In women, the inverse association strengthened and reached statistical significance (HR = 0.63; 95% CI, 0.46-0.87). In analyses restricted to never smokers and nondrinkers of alcohol, inverse associations strengthened in the total cohort (HR = 0.69; 95% CI, 0.52-0.91) and in women (HR = 0.52; 95% CI, 0.37-0.74). There was no coffee-gastric cancer risk association among men, regardless of smoking status or alcohol consumption. Similar results were observed in the nested case-control study after adjustment for H. pylori infection., Conclusion: Daily coffee consumption may reduce the risk of gastric cancer in high-risk populations, especially among women., Impact: Research aimed at identifying the compounds in coffee that may protect against gastric carcinogenesis is warranted.

Background: Cancer is the number one cause of death among men in China. Cigarette smoking is the most preventable cause of cancer. Data on the impact of continued smoking after cancer diagnosis on survival of patients with cancer are sparse., Methods: We studied the association between postdiagnosis smoking and risk of all-cause death among 1,632 incident cancer patients in the Shanghai Cohort Study, a population-based prospective cohort of 18,244 men in Shanghai. The change of smoking status after baseline interview was ascertained through annual in-person interviews. Cox proportional hazards regression models were used to estimate HR and 95% confidence interval (CI) for all-cause mortality associated with change in smoking status., Results: Patients who continued smoking after cancer diagnosis experienced a statistically significant 59% (95% CI, 36-86) increase in risk of death compared with patients with cancer who did not smoke after cancer diagnosis. Among current smokers at cancer diagnosis, HRs (95% CIs) were 1.79 (1.49-2.16) in all patients with cancer, 2.36 (1.63-3.42) in patients with lung cancer, 1.63 (0.98-2.73) in patients with stomach cancer, 2.31 (1.40-3.81) in patients with colorectal cancer, and 2.95 (1.09-7.95) in patients with bladder cancer who continued smoking compared with their counterparts who stopped smoking after cancer diagnosis., Conclusion: Postdiagnosis cigarettes smoking significantly increased the risk of death for male patients with cancer., Impact: These data provide new information about smoking and cancer survival, which should inform future research into the contextual and individual-level barriers that may result in inadequate attention of smoking among patients with cancer in the postdiagnosis setting., (©2013 AACR.)

Background: Rats fed diets deficient in choline develop hepatocellular carcinoma. Tumor DNA from these animals is characteristically hypomethylated, suggesting that disruption of the one-carbon metabolism pathway is an underlying mechanism for hepatocarcinogenesis. Prospective studies in humans on circulating choline and other one-carbon metabolites and hepatocellular carcinoma risk have been lacking., Methods: We prospectively examined the association between prediagnostic serum concentrations of one-carbon metabolites including betaine, choline, cystathionine, homocysteine, methionine, 5-methyltetrahydrofolate (5-MTHF), pyridoxal-5-phosphate (PLP, the bioactive form of vitamin B6) and S-adenosylmethionine (SAM), and risk of developing hepatocellular carcinoma based on a nested case-control study of 297 incident cases and 631 matched controls from a cohort of 18,244 men in Shanghai, China. Logistic regression methods were used to calculate ORs and 95% confidence intervals (CI) adjusted for established risk factors for hepatocellular carcinoma., Results: Serum choline and PLP were associated with statistically significant reduced risk of hepatocellular carcinoma, whereas serum cystathionine, methionine, and SAM were associated with increased hepatocellular carcinoma risk (all Ptrend < 0.05). The inverse associations for hepatocellular carcinoma risk with choline and PLP remained statistically significant after adjusting for all potential confounders. The multivariate-adjusted ORs (95% CIs) for the highest versus lowest quintiles of serum choline and PLP were 0.35 (0.16-0.78; P = 0.010) and 0.44 (0.25-0.78; P = 0.005), respectively. There were no associations for hepatocellular carcinoma risk with 5-MTHF, betaine, or homocysteine., Conclusion: The inverse associations between choline and vitamin B6 and the risk of hepatocellular carcinoma development are novel and warrant further investigation., Impact: Identifying new modifiable factors for hepatocellular carcinoma prevention is warranted.

Background: 4-Aminobiphenyl (ABP) is an established human bladder carcinogen, with tobacco smoke being a major source of human exposure. Other arylamine compounds, including 2,6-dimethylaniline (2,6-DMA), have been implicated as possible human bladder carcinogens. Hemoglobin adducts of 4-ABP and 2,6-DMA are validated biomarkers of exposure to those compounds in humans., Methods: The Shanghai Bladder Cancer Study enrolled 581 incident bladder cancer cases and 604 population controls. Each participant was solicited for his/her history of tobacco use and other lifestyle factors and donation of blood and urine specimens. Red blood cell lysates were used to quantify both hemoglobin adducts of 4-ABP and 2,6-DMA. Urine samples were used to quantify total cotinine. ORs and 95% confidence intervals (CI) for bladder cancer were estimated using unconditional logistic regression methods., Results: Among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for low (below median of positive values) and high versus undetectable levels of 2,6-DMA hemoglobin adducts were 3.87 (1.39-10.75) and 6.90 (3.17-15.02), respectively (Ptrend < 0.001). Similarly, among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for third and fourth versus first/second quartiles of 4-ABP hemoglobin adducts was 1.30 (0.76-2.22) and 2.29 (1.23-4.24), respectively (Ptrend = 0.009). The two associations were independent of each other., Conclusion: Hemoglobin adducts of 4-ABP and 2,6-DMA were significantly and independently associated with increased bladder cancer risk among lifelong nonsmokers in Shanghai, China., Impact: The findings of the present study in China with previous data in Los Angeles, California strongly implicate arylamines as potential causal agents of human bladder cancer.

Background: Mitochondria are eukaryotic organelles responsible for energy production. Quantitative changes in human mitochondrial DNA (mtDNA) copy number have been implicated in various cancer types. Data from prospective cohort studies on mtDNA copy number and colorectal cancer risk have been lacking., Methods: We evaluated the association between mtDNA copy number in peripheral blood and colorectal cancer risk in a nested case-control study of 422 colorectal cancer cases (168 cases with pre-diagnostic blood and 254 cases with post-diagnostic blood) and 874 controls who were free of colorectal cancer among participants of the Singapore Chinese Health Study. The relative mtDNA copy number was measured using real-time PCR. Unconditional logistic regression methods were employed to examine the association between mtDNA copy number and colorectal cancer risk., Results: There was a U-shaped relationship between the relative mtDNA copy number and colorectal cancer risk. Compared with the 2nd quartile, the OR (95% confidence intervals) for subjects in the lowest and highest quartiles of relative mtDNA copy numbers were 1.81 (1.13-2.89) and 3.40 (2.15-5.36), respectively (P(curvilinearity) <0.0001). This U-shaped relationship was present in both men and women, similar for colon cancer and rectal cancer, and independent of the timing of blood draw with regard to cancer diagnosis., Conclusions: This is the first prospectively designed study to show a U-shaped association between the relative mtDNA copy number and risk of colorectal cancer., Impact: The findings of the present study support that mtDNA may play a critical role in the colorectal carcinogenesis in humans., (©2012 AACR)

Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case-control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00-2.88), 1.07 (0.62-1.84), 1.48 (0.86-2.53), and 2.34 (1.33-4.11), respectively, relative to the lowest quartile (P(trend) = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk., (©2011 AACR.)