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Background The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients. Results We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors. Conclusions Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers’ progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase–Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS. Whole-genome sequencing of lung cancer in never smokers identifies different copy number subtypes and shows a lack of tobacco smoking signatures, even in cases exposed to secondhand smoke.

Very few studies have examined sleep duration in relation to cancer incidence with the exception of breast cancer. We assessed the associations between sleep duration and incidences of total and 18 site-specific cancers in the NIH-AARP Health and Diet Study cohort, with 173,327 men and 123,858 women aged 51-72 years at baseline. Self-reported sleep duration categories were assessed via questionnaire. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), using 7-8 hours/night as the reference. We observed a significantly increased risk of stomach cancer among male short sleepers (multivariable HR5-6 vs. 7-8 hours = 1.29; 95%CI: 1.05, 1.59; Ptrend = 0.03). We also observed suggestive associations in either short or long sleepers, which did not reach overall significance (Ptrend >0.05), including increased risks in male short sleepers for cancers of head and neck (HR<5vs.7-8 hours = 1.39; 95%CI:1.00-1.95), bladder (HR5-6vs.7-8 hours = 1.10; 95%CI:1.00-1.20), thyroid (HR<5 vs. 7-8 hours = 2.30; 95%CI:1.06, 5.02), Non-Hodgkin Lymphoma (NHL) (HR5-6vs.7-8 hours = 1.17; 95%CI:1.02-1.33), and myeloma (HR<5vs.7-8 hours = 2.06; 95%CI:1.20-3.51). In women, the suggestive associations include a decreased total cancer risk (HR<5vs.7-8 hours = 0.9; 95%CI:0.83-0.99) and breast cancer risk (HR<5vs.7-8 hours = 0.84; 95%CI:0.71-0.98) among short sleepers. A decreased ovarian cancer risk (HR≥ 9 vs. 7-8 hours = 0.50; 95%CI:0.26-0.97) and an increased NHL risk (HR≥ 9 vs. 7-8 hours = 1.45; 95%CI:1.00-2.11) were observed among long sleepers. In an older population, we observed an increased stomach cancer risk in male short sleepers and suggestive associations with short or long sleep duration for many cancer risks in both genders.

The 60% of patients at highest risk for lung cancer in the National Lung Screening Trial accounted for 88% of the lung-cancer deaths prevented by low-dose CT screening. The use of risk assessment can improve the yield from low-dose CT screening for lung cancer. Lung cancer is the most common cause of cancer-related death in the United States, accounting for 28% and 26% of all cancer deaths among men and women, respectively. 1 Recent results from the National Lung Screening Trial (NLST), which showed a 20% reduction in lung-cancer mortality with low-dose computed tomography (CT) screening, as compared with chest radiography, highlighted the opportunity to reduce the burden of death from lung cancer. 2 With 94 million current and former smokers in the United States, 3 deciding which smokers to target for low-dose CT screening remains an important public health challenge, given the potential costs and harms . . .

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD. Many tumors are known to be heterogeneous. Here, the authors examined multiple samples from 84 patients with lung adenocarcinoma and demonstrate that the intratumor heterogeneity of methylation and copy number associates with poor prognosis.

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 (p<0.001 and fold-change >1.5, 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<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.

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. 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. 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). 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.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank ( N  = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/ MAGI2-AS3 in hippocampus; rs1862416/ TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits ( r g  = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking. There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.

Background The goal of the study was to investigate whether cigarette smoking alters oral and nasal microbial diversity, composition, and structure. Twenty-three current smokers and 20 never smokers were recruited. From each subject, nine samples including supra and subgingiva plaque scrapes, saliva, swabs from five soft oral tissue sites, and one nasal swab from both the anterior nares were collected. 16S rRNA V3-V4 region was sequenced for microbial profiles. Results We found that alpha diversity was lower in smokers than in nonsmokers in the buccal mucosa, but in other sample sites, microbial diversity and composition were not significantly different by smoking status. Microbial profiles differed significantly among eight oral sites. Conclusions This study investigates the effect of cigarette smoking on different sites of the oral cavity and shows a potential effect of cigarette smoking on the buccal mucosa microbiota. The marked heterogeneity of the oral microbial ecosystem that we found may contribute to the stability of the oral microbiota in most sites when facing environmental perturbations such as that caused by cigarette smoking.

Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking. The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5-2.5), emphysema (OR = 1.9, 95% CI = 1.4-2.8), or COPD (OR = 2.5, 95% CI = 2.0-3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30-0.78). These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.