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Background We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test. Methods We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided. Results The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (P difference =.001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model. Conclusion Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung. [ABSTRACT FROM AUTHOR]

Background: The role of smoking in nasopharyngeal carcinoma (NPC) remains uncertain, especially in endemic regions. We conducted an individual participant data (IPD) meta-analysis of prospective cohort studies to investigate the associations between smoking exposure and risk of NPC.Methods: We obtained individual participant data of 334 935 male participants from six eligible population-based cohorts in NPC-endemic regions, including two each in Guangzhou and Taiwan, and one each in Hong Kong and Singapore. We used one- and two-stage approaches IPD meta-analysis and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of NPC for smoking exposure adjusting for age and drinking status.Results: During 2 961 315 person-years of follow-up, 399 NPC evens were ascertained. Risks of NPC were higher in ever versus never smokers (HRone-stage = 1.32, 95% CI = 1.07-1.63, P = 0.0088; HRtwo-stage = 1.27, 1.01-1.60, 0.04). These positive associations appeared to be stronger in ever smokers who consumed 16+ cigarettes/day (HRone-stage = 1.67, 95% CI = 1.29-2.16, P = 0.0001), and in those who started smoking at age younger than 16 (2.16, 1.33-3.50, 0.0103), with dose-response relationships (P-values for trend = 0.0028 and 0.0103, respectively). Quitting (versus daily smoking) showed a small reduced risk (stopped for 5+ years: HRone-stage = 0.91, 95% CI = 0.60-1.39, P = 0.66; for former smokers: HRtwo-stage = 0.84, 0.61-1.14, 0.26).Conclusions: This first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational evidence that smoking increased NPC risk in men. NPC should be added to the 12-16 cancer sites known to be tobacco-related cancers. Strong tobacco control policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions. [ABSTRACT FROM AUTHOR]

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case–control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8- epi -prostaglandin F2α (8- epi -PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8- epi- PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8- epi- PGF2α were 2.55 (95% confidence interval = 1.62–4.01, P trend < 0.001). This positive 8- epi -PGF2α–HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes. [ABSTRACT FROM AUTHOR]

It has been hypothesized that the pathogenesis of lung cancer induced by cigarette smoking involves oxidative damage by free radicals. Epidemiological data on biomarkers of oxidative damage and risk of lung cancer development are sparse. A nested case-control study of 610 lung cancer cases and 610 matched controls was conducted within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2 (8-epiPGF2), a biomarker of oxidative stress, were determined in baseline urine samples using a validated mass-spectrometry assay. Current smokers had significantly higher level of 8-epiPGF2 than former smokers or never smokers (P < 0.001). 8-epiPGF2 levels were significantly higher in lung cancer cases than their smoking-matched controls in former and current smokers, but not different in never smokers (P for interaction = 0.019). The relative risks of developing lung cancer for former and current smokers in the highest relative to the lowest quartile of 8-epiPGF2 were 5.25 (P trend = 0.035) and 1.99 (P trend =0.007), respectively. The effect of 8-epiPGF2 and biomarkers of cigarette smoke exposure on lung cancer risk was additive; the relative risk was 5.33 (95% confidence interval = 2.65-7.51) for current smokers with the highest thirds of 8-epiPGF2 and total cotinine compared with their lowest thirds. Smokers with a heightened state of oxidative stress in response to the insults of cigarette smoking may be more susceptible to smoking-induced lung carcinogenesis. [ABSTRACT FROM AUTHOR]

Exposures to polycyclic aromatic hydrocarbons (PAHs) from various environmental and occupational sources are considered a primary risk factor for lung cancer among lifelong never smokers, based largely on results from epidemiologic studies utilizing self-reported exposure information. Prospective, biomarker-based human studies on the role of PAH and other airborne carcinogens in the development of lung cancer among lifelong non-smokers have been lacking. We prospectively investigated levels of urinary metabolites of a PAH and volatile organic compounds in relation to lung cancer risk in a nested case–control study of 82 cases and 83 controls among lifelong never smokers of the Shanghai Cohort Study, a prospective cohort of 18 244 Chinese men aged 45–64 years at enrollment. We quantified three PAH metabolites: r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), 3-hydroxyphenanthrene (3-OH-Phe) and total hydroxyphenanthrenes (total OH-Phe, the sum of 1-, 2-, 3- and 4-OH-Phe), as well as metabolites of the volatile organic compounds acrolein (3-hydroxypropyl mercapturic acid), benzene (S-phenyl mercapturic acid), crotonaldehyde (3-hydroxy-1-methylpropylmercapturic acid) and ethylene oxide (2-hydroxyethyl mercapturic acid). Urinary cotinine was also quantified to confirm non-smoking status. Compared with the lowest quartile, odds ratios (95% confidence intervals) for lung cancer risk for the highest quartile levels of PheT, 3-OH-Phe and total OH-Phe were 2.98 (1.13–7.87), 3.10 (1.12–7.75) and 2.59 (1.01–6.65) (all Ptrend < 0.05), respectively. None of the metabolites of the volatile organic compounds were associated with overall lung cancer risk. This study demonstrates a potentially important role of exposure to PAH in the development of lung cancer among lifelong never smokers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Besides polycyclic aromatic hydrocarbons (PAH) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which are established lung carcinogens, tobacco smoke also contains relatively large quantities of volatile organic carcinogens and toxicants, including 1,3-butadiene, ethylene oxide, benzene, acrolein and crotonaldehyde. Although animal experiments showed that some of these compounds can induce tumors in multiple organs including the lung, epidemiological studies of their relationship with lung cancer in smokers have not been reported. Therefore, in this study, we quantified urinary mercapturic acid metabolites of 1,3-butadiene, ethylene oxide, benzene, acrolein and crotonaldehyde in addition to urinary biomarkers for PAH, NNK and nicotine in 343 lung cancer cases and 392 matched controls among a cohort of 18 244 Chinese men in Shanghai, China, followed from 1986 to 2006. Compared with the lowest quartiles, highest quartiles of all measured mercapturic acids were associated with statistically significantly ∼2-fold increased risk for lung cancer (all P’s for trend <0.01) after adjustment for smoking intensity and duration. The positive associations between biomarkers of ethylene oxide, benzene or acrolein and lung cancer risk remained statistically significant after adjustment for biomarkers of PAH and NNK, whereas urinary total cotinine completely explained the mercapturic acid metabolites and lung cancer associations (all P’s for trend ≥0.39). We conclude that mercapturic acid metabolites of 1,3-butadiene, ethylene oxide, benzene, acrolein and crotonaldehyde may not be independent risk predictors of lung cancer among Shanghai smokers, in contrast to biomarkers of PAH, NNK and nicotine exposure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

N′-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are tobacco-specific nitrosamines. NNN and NNK can induce cancers of the esophagus and lung, respectively, in laboratory animals, but data on human esophageal cancer are lacking. The association between levels of NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), an NNK metabolite, in urine samples collected before diagnosis and risk of esophageal cancer was examined in 77 patients with esophageal cancer and 223 individually matched controls, all current smokers, from a cohort of 18244 Chinese men in Shanghai, China, followed from 1986 to 2008. Urinary total NNN (free NNN plus NNN-N-glucuronide) was significantly higher, whereas the percentage of its detoxification product NNN-N-glucuronide was significantly lower in cases than controls. Odds ratios (95% confidence intervals) of esophageal cancer for the second and third tertiles of total NNN were 3.99 (1.25–12.7) and 17.0 (3.99–72.8), respectively, compared with the first tertile after adjustment for urinary total NNAL and total cotinine and smoking intensity and duration (Ptrend < 0.001). The corresponding figures for the percentage of NNN-N-glucuronides were 0.37 (0.17–0.80) and 0.27 (0.11–0.62) (Ptrend = 0.001). Urinary total NNN and the percentage of NNN-N-glucuronides almost completely accounted for the observed association for urinary total NNAL (free NNAL plus its glucuronides), urinary total cotinine and smoking intensity with esophageal cancer risk. These findings along with results of previous studies in laboratory animals support a significant and unique role of NNN in esophageal carcinogenesis in humans. [ABSTRACT FROM AUTHOR]

Although there is some epidemiologic evidence that soy may reduce risk of osteoporotic fracture in women, it is not known whether this risk reduction also occurs for men. The authors examined gender-specific associations between soy intake and hip fracture risk in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese living in Singapore. At recruitment between 1993 and 1998, each subject was administered a food frequency questionnaire and questions on medical history and lifestyle factors. As of December 31, 2006, 276 incident cases of hip fracture in men and 692 cases in women were identified via linkage with hospital discharge databases. For both genders, hip fracture risk was positively associated with cigarette smoking and was inversely associated with body mass index. There was a statistically significant association of tofu equivalents, soy protein, and isoflavones with hip fracture risk among women but not among men. Compared with women in the lowest quartile of intakes for tofu equivalents (<49.4 g/day), soy protein (<2.7 g/day), and isoflavones (<5.8 mg/1,000 kcal/day), those in the second–fourth quartiles exhibited 21%–36% reductions in risk (all P < 0.036). Risk levels were comparable across the second, third, and fourth quartiles of soy intake categories. [ABSTRACT FROM PUBLISHER]