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Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk., (Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.)

Background: In Xuanwei County, Yunnan Province, China, lung cancer mortality rates in both males and females are among the highest in China., Methods: We evaluated differential effects of smoking on lung cancer mortality before and after household stove improvement with chimney to reduce exposure to smoky coal emissions in the unique cohort in Xuanwei, China. Effects of independent variables on lung cancer mortality were measured as hazard ratios and 95% confidence intervals using a multivariable Cox regression model that included separate time-dependent variables for smoking duration (years) before and after stove improvement., Results and Conclusion: We found that the effect of smoking on lung cancer risk becomes considerably stronger after chimney installation and consequent reduction of indoor coal smoke exposure.

Epstein-Barr virus (EBV) has remained the main candidate suggested as the infection causing Hodgkin's lymphoma for several years. However, EBV genome has been found only within the tumor in about 20%-40% of Hodgkin's lymphoma cases with a prior diagnosis of infectious mononucleosis. Recently, autoimmune and related conditions have drawn attention to a potential role for immune-related and inflammatory conditions in the etiology and pathogenesis of the malignancy. Evidence from multiple affected families from case series, a twin study, a case-control study, and population-based registry studies implicate a role for genetic factors. Simultaneously, data from Eastern Asia and among Chinese immigrants in North America indicate increasing incidence trends for Hodgkin's lymphoma being associated with westernization. These results emphasize an interaction between environmental and genetic risk factors in Hodgkin's lymphoma.

We examined CYP1A1 (I462V) and GSTM1 null polymorphisms in 200 female cases and 144 female controls selected from a population-based case-control study of lung cancer conducted in northeast China, where the rates of lung cancer among Chinese women are especially high. The CYP1A1 codon 462 point mutation in exon 7 (I462V) causes an Ile-Val substitution near the heme binding site. This mutation correlates with inducibility of aryl hydrocarbon hydrolase (AHH) activity, which activates polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke and in indoor air pollution from coal-burning stoves, a risk factor for lung cancer in this study population. We found that the CYP1A1 I462V genotype (combined ile/val and val/val) was significantly associated with lung cancer risk. The odds ratio (OR) was 2.5 (95% confidence interval [CI], 1.55-4.03) after adjustment for significant risk factors such as age, ever smoking status, family history of cancer, and eye irritation when cooking. The association was more pronounced among non-smokers (OR=3.67; 95% CI, 1.85-7.28) than among smokers (OR=1.74, 95% CI, 0.85-3.54). In contrast, we did not find a significant association with the GSTM1 null genotype. In summary, our case-control study of lung cancer among women in northeast China revealed an elevated risk associated with the CYP1A1 I462V genotype, but no interaction with smoking or indoor air pollution was found.

Multiple studies in the general population have suggested that subjects with the glutathione S-transferase M1 (GSTM1)-null genotype, who lack functional GSTM1, are at higher risk for bladder cancer. To evaluate the impact of the GSTM1-null genotype on bladder cancer caused by occupational exposure to benzidine and to determine its influence on benzidine metabolism, we carried out three complementary investigations: a case-control study of bladder cancer among workers previously exposed to benzidine in China, a cross-sectional study of urothelial cell DNA adducts and urinary mutagenicity in workers currently exposed to benzidine in India, and a laboratory study of the ability of human GSTM1 to conjugate benzidine and its known metabolites in vitro. There was no overall increase in bladder cancer risk for the GSTM1-null genotype among 38 bladder cancer cases and 43 controls (odds ratio, 1.0; 95% confidence interval, 0.4-2.7), although there was some indication that highly exposed workers with the GSTM1-null genotype were at greater risk of bladder cancer compared to similarly exposed workers without this allele. However, the GSTM1 genotype had no impact on urothelial cell DNA adduct and urinary mutagenicity levels in workers currently exposed to benzidine. Furthermore, human GSTM1 did not conjugate benzidine or its metabolites. These results led us to conclude that the GSTM1-null genotype does not have an impact on bladder cancer caused by benzidine, providing a contrast to its association with elevated bladder cancer risk in the general population.

The wide variations in urinary bladder and colo-rectal cancer incidence in humans have been attributed in part to metabolic factors associated with exposure to carcinogenic aromatic and heterocyclic amines. Cytochrome P-4501A2 (CYP1A2), which catalyses N-oxidation, and acetyltransferase (NAT2) which catalyses N- and O-acetylation, both appear to be polymorphically distributed in human populations; and slow and rapid NAT2 phenotypes have been implicated as risk factors for these cancers. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. For the NAT2 phenotype, we confirm the valid use of the urinary molar ratio of AFMU/1-methylxanthine, even in alkaline urines. For the CYP1A2 phenotype, the urinary molar ratio of [1,7-dimethylxanthine + 1,7-dimethyluric acid]/caffeine, taken at 4-5 h after caffeine ingestion, was identified from pharmacokinetic analyses of 12 subjects as being better correlated (r = 0.73; p = 0.007) with the rate constant for caffeine 3-demethylation than other previously suggested ratios. This procedure was then used to determine the CYP1A2 phenotype in subjects from Arkansas (n = 101), Italy (n = 95), and China (n = 78). Statistical and probit analyses of nonsmokers indicated that the CYP1A2 activity was not normally distributed and appeared trimodal. This trimodality allowed arbitrary designation of slow, intermediate, and rapid phenotypes, which ranged from 12-13% slow, 51-67% intermediate, and 20-37% rapid, in the different populations. A reproducibility study of 13 subjects over a 5 day or 5 week period showed that, with one exception, intraindividual variability did not alter this CYP1A2 phenotypic classification. Induction of CYP1A2 by cigarette smoking was also confirmed by the increased caffeine metabolite ratios observed in the Arkansas and Italian smokers (blonde tobacco). However, Italian smokers of black tobacco and Chinese smokers did not appear to be induced. Furthermore, probit analyses of Arkansas and Italian blonde tobacco smokers could not discriminate between phenotypes, apparently as a consequence of enzyme induction.