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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.)

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.)

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.)

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)

Background: Environmental tobacco smoke (ETS) contains tobacco carcinogens. Hepatic cytochrome P450 (CYP) 1A2 and N-acetyltransferase (NAT2) are important isoenzymes in activation and detoxification, respectively, of tobacco carcinogens. Data on ETS and bladder cancer risk are sparse., Methods: We examined the effects of ETS alone and combined with NAT2/CYP1A2 on bladder cancer risk among lifelong-nonsmokers in a case-control study involving 195 patients and 261 controls in Shanghai, China. A comprehensive history of ETS exposure was determined through in-person interviews while CYP1A2 and NAT2 phenotypes by a caffeine-based urinary assay., Results: ETS exposure was related to an overall statistically nonsignificant 38% increased bladder cancer risk. The risk increased with increasing number of cigarettes smoked by household members or number of hours per day at workplace where coworkers smoked. Compared with no ETS exposure, subjects living with smoking parents during childhood had an OR of 2.43 (95% CI = 0.99-5.96) for bladder cancer. When all ETS sources were combined, the risk increased with increasing total ETS score (P(trend) = 0.03). The OR for high versus nil ETS exposure was 3.00 (95% CI = 1.24-7.26). The increased risk with ETS was mainly seen among individuals possessing a CYP1A2 high efficiency and/or a NAT2 slow acetylation phenotype (P(trend) = 0.04)., Conclusions: ETS was associated with an increased bladder cancer risk for lifelong-nonsmokers. The association was stronger for people possessing the at-risk phenotypes of CYP1A2 and/or NAT2., Impact: Reducing exposure to ETS for children and genetically more susceptible individuals could be more effective for bladder cancer prevention., (©2010 AACR.)

Background: Epidemiologic findings of tobacco and alcohol use in relation to gastric cancer are inconsistent. Well-designed prospective studies examining their relationship are sparse., Methods: The association between cigarette smoking/alcohol intake and gastric cancer risk was examined in a population-based prospective cohort of 18,244 middle-aged and older men in Shanghai, China, who were enrolled in the study during 1986-1989. After up to 20 years of follow-up, 391 incident gastric cancer cases were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI)., Results: Ever smokers experienced a statistically significant increased risk of gastric cancer (HR, 1.59; 95% CI, 1.27-1.99) compared with nonsmokers after adjustment for alcohol intake and other confounders. Among nondrinkers, smokers experienced 80% increased risk of gastric cancer (HR, 1.81; 95% CI,1.36, 2.41). Conversely, heavy drinkers experienced a statistically significant increase in risk of gastric cancer (HR, 1.46; 95% CI, 1.05-2.04) among all subjects and a statistically nonsignificant 80% increased risk among never smokers. Further adjustment for Helicobacter pylori serology, serum levels of beta-carotene and vitamin C, and urinary level of total isothiocyanates in combination with glutathione S-transferase (GST) M1 and GSTT1 genotypes did not materially change the associations between smoking/alcohol consumption and gastric cancer risk., Conclusions: These results suggest that cigarette smoking and alcohol consumption may exert independent effects on the development of gastric cancer in this high-risk population., Impact: Modification of these lifestyle choices may reduce the incidence of gastric cancer., ((c)2010 AACR.)

Background: Epidemiologic studies associate lung cancer in nonsmoking Chinese women with Chinese-style wok cooking. Our goal was to quantify carcinogen and toxicant biomarkers in Chinese women who reported regularly doing home cooking compared with women randomly selected from the Singapore Chinese Health Study as controls., Methods: Biomarkers were quantified by high-performance liquid chromatography-mass spectrometry, high-performance liquid chromatography with fluorescence detection, and gas chromatography-mass spectrometry., Results: Compared with controls, women who engaged in regular home cooking had significantly higher levels of mercapturic acids of acrolein {geometric mean, 1,959 pmol/mg creatinine [95% confidence interval (95% CI), 1,554-2,467] versus 1,370 (95% CI, 1,077-1,742); P=0.038}, crotonaldehyde [geometric mean, 232 pmol/mg creatinine (95% CI, 193-277) versus 142 (95% CI, 118-171); P=0.0004], and benzene [geometric mean, 0.58 pmol/mg creatinine (95% CI, 0.44-0.78) versus 0.18 (95% CI, 0.14-0.24); P<0.0001]. No significant differences were found in levels of mercapturic acids of 1,3-butadiene, metabolites of pyrene and phenanthrene, or acetaldehyde-leukocyte DNA adduct levels between the groups. Levels of the ethylene oxide mercapturic acid were significantly higher in the controls., Conclusions: The higher levels of the mercapturic acid of benzene, a multiorgan carcinogen, in the women who cooked are particularly notable. Overall, the results showing increased exposure to the volatile toxicants and carcinogens acrolein, crotonaldehyde, and benzene in Chinese women who regularly cook provide a plausible lead for further investigating the role of volatile compounds generated during high-temperature cooking with oils as causes of lung cancer., Impact: A new direction for research on lung cancer etiology is suggested., (Copyright (c) 2010 AACR)

Lung cancer among nonsmokers has emerged as a distinct clinicopathologic entity for which the etiology is still poorly understood, but which accounts for a significant proportion of the lung cancers among women. Although estrogens have been shown to have mitogenic effects in lung cells and interact with growth factor pathways in tumorigenesis, epidemiologic evidence for a link between reproductive hormones and lung cancer is sparse and inconsistent. We examined the effect of parity, age at menarche/menopause, cycle length and use of exogenous hormones, and dietary soy and soy isoflavonoid intake on lung cancer risk in a prospective cohort of middle-aged and elderly Chinese women in Singapore among whom 91% were lifetime nonsmokers. Among 35,298 women (mean follow-up time, 9.6 years), 298 cases of incident lung cancer were recorded, of which 189 (63.4%) occurred in nonsmokers. Compared with nulliparous women, those with one to two, three to four, and more than five livebirths had relative risks of between 0.49 and 0.59 (P for trend<0.01) for all lung cancers, and between 0.32 and 0.42 (P for trend<0.001) for adenocarcinomas. This relationship was observed in both smokers and nonsmokers. Age at menarche and menopause did not seem to influence risk. Dietary soy isoflavonoid intake was associated with a statistically significant inverse trend among nonsmokers only (relative risks, 0.59 for highest versus lower quartile; P for trend, 0.021). These findings add support for the role of hormonal factors in the etiology of lung cancer among nonsmoking women, and are consistent with emerging experimental evidence in this regard.

There is increasing evidence from observational studies that breast cancer risk is inversely associated with soy and green tea consumption. We investigated the effects of these two dietary agents on mammographic density, a well-established biomarker for breast cancer risk, in a cross-sectional analysis of mammograms and validated food frequency questionnaires from 3,315 Chinese women in Singapore. Percent mammographic density (PMD) was assessed using a reproducible computer-assisted method. We used generalized linear models to estimate PMD by intake of soy, green tea, and black tea while adjusting for potential confounders. Daily green tea drinkers showed statistically significantly lower PMD (19.5%) than non-tea drinkers (21.7%; P = 0.002) after adjusting for relevant covariates. This difference in PMD between daily green tea drinkers and non-tea drinkers remained statistically significant after adjustment for soy (P = 0.002); the effect was more apparent among lower soy consumers (Q1-Q3; 21.9% versus 19.4%; P = 0.002) than in higher (Q4) consumers (20.9% versus 19.5%; P = 0.32). Black tea intake was unrelated to PMD. Only among postmenopausal women who reported very high soy intake (Q4) compared with those with less soy intake was there any association noted between PMD and soy intake (18.9% versus 20.5%; P = 0.035). Following adjustment for green tea intake, the association between soy and PMD was no longer statistically significant (P = 0.52). Our findings suggest that both regular green tea and high soy intake may have beneficial effects on the breast; the effect of green tea on PMD may be stronger than the effect of soy.

Laboratory and epidemiologic evidence suggests that dietary isothiocyanates (ITCs) may have a chemopreventive effect on cancer. Humans are exposed to ITCs primarily through ingestion of cruciferous vegetables that contain glucosinolates, the precursors to ITCs. The association between urinary total ITC level and colorectal cancer risk was examined in a cohort of 18,244 men in Shanghai, China, with 16 years of follow-up. Urinary total ITCs were quantified on 225 incident cases of colorectal cancer and 1,119 matched controls. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated using logistic regression models. High levels of urinary total ITCs were associated with a reduced risk of colorectal cancer 5 years after baseline measurements of ITCs, whereas a statistically nonsignificant increase in the risk of colorectal cancer was observed for cases within 5 years of post-enrollment (OR, 1.93; 95% CI, 0.85-4.39 for the upper three quartiles of urinary ITCs versus the lowest quartile). The inverse ITC-colorectal cancer association became stronger with a longer duration of follow-up. Compared with the first quartile, ORs (95% CIs) for the second, third, and fourth quartiles of total ITCs in urine collected 10 or more years before cancer diagnosis were 0.61 (0.35-1.05), 0.51 (0.29-0.92), and 0.46 (0.25-0.83), respectively, for risk of colorectal cancer (P for trend = 0.006). The present study suggests that dietary ITCs may exert tumor inhibitory effects, especially during earlier stages of the multistage process of carcinogenesis.

Carcinogenic heterocyclic aromatic amines (HAA) are formed in cooked meats, poultry, and fish and arise in tobacco smoke. We measured the concentrations of four prevalent HAAs in spot urine samples collected at baseline from 170 participants of the Shanghai Cohort study, a population-based cohort study of adult men recruited during 1986 to 1989 in Shanghai, China. Sixteen (18.6%) of 86 nonsmokers were positive for urinary 2-amino-9H-pyrido[2,3-b]indole (AalphaC) versus 41 (48.8%) of 84 cigarette smokers; the difference was statistically significant (P < 0.001). The number of cigarettes smoked per day was positively and significantly related to urinary levels of AalphaC in study subjects (P < 0.001); the mean level among nonsmokers was 2.54 ng/g creatinine, whereas the means for light (1-19 cigarettes per day) and heavy (20+ cigarettes per day) smokers were 7.50 and 11.92 ng/g creatinine, respectively. 2-Amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline was undetected in the urine of the 170 subjects. Only 5 (2.9%) and 6 (3.5%) subjects, respectively, showed detectable levels of urinary 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and smoking status was unrelated to levels of either HAA. Quantitative measurements of HAAs in commonly eaten pork and chicken dishes in Shanghai showed low concentrations of HAAs (<1 ng/g meat). Our data indicate that AalphaC represents a major HAA exposure in adult men of Shanghai, China, and that tobacco smoke is an important point source of their AalphaC exposure.

Background: High body mass index (BMI) and diabetes have been linked to risk of non-Hodgkin's lymphoma (NHL), but results are inconsistent and most studies use self-reported information. No study has evaluated the association of NHL with postload plasma glucose (PLG) levels, which are positively associated with BMI. We analyzed data from a cohort study to investigate associations of interviewer-measured BMI and PLG with risk of NHL mortality and to explore associations with leukemia and multiple myeloma., Methods: Employees of 84 Chicago-area organizations, with an average age of 40 years at baseline, were screened from 1967 to 1973. Height and weight were measured by study nurses. A 50-g oral glucose load was administered to nondiabetic participants. Of the at-risk cohort of 35,420 men and women, 129 died of NHL, 151 died of leukemia, and 66 died of multiple myeloma during an average of 31 years of follow-up. Hazard Ratios (HR) and 95% confidence intervals (95% CI) were derived from Cox proportional hazards regression models., Results: Among men, there were positive dose-response relations of BMI with mortality from NHL (HR, 2.57; 95% CI, 1.24-5.34 for the highest versus lowest quartile; P(trend) = 0.01) and leukemia (HR, 1.98; 1.07-3.69; P(trend) = 0.02). PLG also was positively related to NHL mortality (HR, 2.86; 95% CI, 1.35-6.06 for the highest versus lowest category; P(trend) = 0.004). For women, a higher BMI was positively associated with leukemia mortality (HR, 2.47; 95% CI, 0.96-6.36; P(trend) = 0.02) and the highest level of PLG was associated with risk of mortality from multiple myeloma (HR, 3.06; 95% CI, 1.05-8.93). The risk estimates for BMI and PLG remained unchanged after adjustment for each factor., Conclusions: High BMI and/or abnormal PLG is associated with higher risk of mortality from NHL and possibly leukemia and from myeloma in women. These findings might have public health significance because BMI and glucose levels are amenable to modification.