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OBJECTIVE:Cohort studies in Europe, but not in North-America, showed an association between exposure to outdoor particulate matter with aerodynamic diameter ≤10 μm (PM10) and lung cancer risk. Only a case-control study on lung cancer and PM10 in South Korea has so far been performed. For the first time in Europe we analyzed quantitatively this association using a case-control study design in highly polluted areas in Italy. METHODS:The Environment And Genetics in Lung cancer Etiology (EAGLE) study, a population-based case-control study performed in the period 2002-2005 in the Lombardy Region, north-west Italy, enrolled 2099 cases and 2120 controls frequency-matched for area of residence, gender, and age. For this study we selected subjects with complete active and passive smoking history living in the same municipality since 1980 until study enrollment. Fine resolution annual PM10 estimates obtained by applying land use regression modeling to satellite data calibrated with fixed site monitor measurements were used. We assigned each subject the PM10 average estimates for year 2000 based on enrollment address. We used logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for matching variables, education, smoking, and dietary and occupational variables. RESULTS:We included 3473 subjects, 1665 cases (1318 men, 347 women) and 1808 controls (1368 men, 440 women), with PM10 individual levels ranging from 2.3 to 53.8 μg/m3 (mean: 46.3). We found increasing lung cancer risk with increasing PM10 category (P-value for trend: 0.04). The OR per 10 μg/m3 was 1.28 (95% CI: 0.95-1.72). The association appeared stronger for squamous cell carcinoma (OR 1.44, 95% CI: 0.90-2.29). CONCLUSION:In a population living in highly polluted areas in Italy, our study added suggestive evidence of a positive association between PM10 exposure and lung cancer risk. This study emphasizes the need to strengthen policies to reduce airborne pollution.

BACKGROUND:Blood pressure (BP) is a complex, multifactorial clinical outcome driven by genetic susceptibility, behavioral choices, and environmental factors. Many molecular mechanisms have been proposed for the pathophysiology of high BP even as its prevalence continues to grow worldwide, increasing morbidity and marking it as a major public health concern. To address this, we evaluated miRNA profiling in blood leukocytes as potential biomarkers of BP and BP-related risk factors. METHODS:The Beijing Truck Driver Air Pollution Study included 60 truck drivers and 60 office workers examined in 2008. On two days separated by 1-2 weeks, we examined three BP measures: systolic, diastolic, and mean arterial pressure measured at both pre- and post-work exams for blood NanoString nCounter miRNA profiles. We used covariate-adjusted linear mixed-effect models to examine associations between BP and increased miRNA expression in both pooled and risk factor-stratified analyses. RESULTS:Overall 43 miRNAs were associated with pre-work BP (FDR

BACKGROUND: De novo tumors (DNT) after liver transplantation (LT) represent a growing concern. PATIENTS AND METHODS: We analyzed the incidence of DNT, type, time of onset, risk factors and mortality (as of 2010) in 494 adult patients transplanted in the last 26 years (1983-2009). RESULTS: DNT occurred in 41 (8.3%) of the patients. The Standardized Incidence Ratio (SIR) compared with the Italian population was 1.8. There was a higher incidence in males (SIR 2.0), an expected extremely high rate of Kaposi's sarcoma (SIR 127.95) and unexpected higher rates of tumors of the bladder in males (SIR 3.3). The incidence of DNT was higher within the first two years of LT (SIR 2.7) for Kaposi's sarcoma (SIR 393.3) and after 10 years (SIR 1.7) for bladder tumors (SIR 10.6). Multivariate analysis identified alcoholic cirrhosis (HR = 3.0, 95% CI = 1.2-7.8) and sclerosing cholangitis (HR = 3.5, 95% CI = 1.1-11.3) in the recipient as main risk factors for the occurrence of DNT. CONCLUSIONS: Surveillance protocols for DNT must be specifically oriented to patients transplanted for alcoholic cirrhosis and sclerosing cholangitis. They should focus on early detection of Kaposi's sarcomas, and more remarkably, on late development bladder tumors in men after LT.

DNA methylation is an epigenetic mechanism that has been increasingly investigated in observational human studies, particularly on blood leukocyte DNA. Characterizing the degree and determinants of DNA methylation stability can provide critical information for the design and conduction of human epigenetic studies.We measured DNA methylation in 12 gene-promoter regions (APC, p16, p53, RASSF1A, CDH13, eNOS, ET-1, IFNγ, IL-6, TNFα, iNOS, and hTERT) and 2 of non-long terminal repeat elements, i.e., L1 and Alu in blood samples obtained from 63 healthy individuals at baseline (Day 1) and after three days (Day 4). DNA methylation was measured by bisulfite-PCR-Pyrosequencing. We calculated intraclass correlation coefficients (ICCs) to measure the within-individual stability of DNA methylation between Day 1 and 4, subtracted of pyrosequencing error and adjusted for multiple covariates.Methylation markers showed different temporal behaviors ranging from high (IL-6, ICC = 0.89) to low stability (APC, ICC = 0.08) between Day 1 and 4. Multiple sequence and marker characteristics were associated with the degree of variation. Density of CpG dinucleotides nearby the sequence analyzed (measured as CpG(o/e) or G+C content within ±200 bp) was positively associated with DNA methylation stability. The 3' proximity to repeat elements and range of DNA methylation on Day 1 were also positively associated with methylation stability. An inverted U-shaped correlation was observed between mean DNA methylation on Day 1 and stability.The degree of short-term DNA methylation stability is marker-dependent and associated with sequence characteristics and methylation levels.

Chronic occupational exposure to benzene is associated with an increased risk of hematological malignancies such as acute myeloid leukemia (AML), but the underlying mechanisms are still unclear. The main objective of this study was to investigate the association between benzene exposure and DNA methylation, both in repeated elements and candidate genes, in a population of 158 Bulgarian petrochemical workers and 50 unexposed office workers. Exposure assessment included personal monitoring of airborne benzene at work and urinary biomarkers of benzene metabolism (S-phenylmercapturic acid [SPMA] and trans,trans-muconic acid [t,t-MA]) at the end of the work-shift. The median levels of airborne benzene, SPMA and t,t-MA in workers were 0.46 ppm, 15.5 µg/L and 711 µg/L respectively, and exposure levels were significantly lower in the controls. Repeated-element DNA methylation was measured in Alu and LINE-1, and gene-specific methylation in MAGE and p15. DNA methylation levels were not significantly different between exposed workers and controls (P>0.05). Both ordinary least squares (OLS) and beta-regression models were used to estimate benzene-methylation associations. Beta-regression showed better model specification, as reflected in improved coefficient of determination (pseudo R(2)) and Akaike's information criterion (AIC). In beta-regression, we found statistically significant reductions in LINE-1 (-0.15%, P

Mood disorders may affect lung cancer risk. We evaluated this hypothesis in two large studies.We examined 1,939 lung cancer cases and 2,102 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in Italy (2002-2005), and 82,945 inpatients with a lung cancer diagnosis and 3,586,299 person-years without a lung cancer diagnosis in the U.S. Veterans Affairs Inpatient Cohort (VA study), composed of veterans with a VA hospital admission (1969-1996). In EAGLE, we calculated odds ratios (ORs) and 95% confidence intervals (CI), with extensive adjustment for tobacco smoking and multiple lifestyle factors. In the VA study, we estimated lung cancer relative risks (RRs) and 95% CIs with time-dependent Poisson regression, adjusting for attained age, calendar year, hospital visits, time within the study, and related previous medical diagnoses. In EAGLE, we found decreased lung cancer risk in subjects with a personal history of mood disorders (OR: 0.59, 95% CI: 0.44-0.79, based on 121 lung cancer incident cases and 192 controls) and family history of mood disorders (OR: 0.62, 95% CI: 0.50-0.77, based on 223 lung cancer cases and 345 controls). The VA study analyses yielded similar results (RR: 0.74, 95% CI: 0.71-0.77, based on 2,304 incident lung cancer cases and 177,267 non-cancer person-years) in men with discharge diagnoses for mood disorders. History of mood disorders was associated with nicotine dependence, alcohol and substance use and psychometric scales of depressive and anxiety symptoms in controls for these studies.The consistent finding of a relationship between mood disorders and lung cancer risk across two large studies calls for further research into the complex interplay of risk factors associated with these two widespread and debilitating diseases. Although we adjusted for smoking effects in EAGLE, residual confounding of the results by smoking cannot be ruled out.

Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations.

Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p