Christopher Amos and colleagues perform genome-wide association analysis for lung cancer using cohorts genotyped on the OncoArray and combing these with existing data. They identify 18 loci, 10 of which are new, finding heterogeneity across the different lung cancer subtypes, and explore candidate genes through eQTL analysis in lung tissue. Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

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<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.

Aberrant DNA methylation patterns, including global hypomethylation, gene-specific hypermethylation/hypomethylation, and loss of imprinting (LOI), are common in acute myelogenous leukemia (AML) and other cancer tissues. We investigated for the first time whether such epigenetic changes are induced in healthy subjects by low-level exposure to benzene, a widespread pollutant associated with AML risk. Blood DNA samples and exposure data were obtained from subjects with different levels of benzene exposure, including 78 gas station attendants, 77 traffic police officers, and 58 unexposed referents in Milan, Italy (personal airborne benzene range, 0.20). This is the first human study to link altered DNA methylation, reproducing the aberrant epigenetic patterns found in malignant cells, to low-level carcinogen exposure. [Cancer Res 2007;67(3):876–80]

Follow-up of the population exposed to dioxin after the 1976 accident in Seveso, Italy, was extended to 1996. During the entire observation period, all-cause and all-cancer mortality did not increase. Fifteen years after the accident, mortality among men in high-exposure zones A (804 inhabitants) and B (5,941 inhabitants) increased from all cancers (rate ratio (RR) = 1.3, 95% confidence interval (CI): 1.0, 1.7), rectal cancer (RR = 2.4, 95% CI: 1.2, 4.6), and lung cancer (RR = 1.3, 95% CI: 1.0, 1.7), with no latency-related pattern for rectal or lung cancer. An excess of lymphohemopoietic neoplasms was found in both genders (RR = 1.7, 95% CI: 1.2, 2.5). Hodgkin's disease risk was elevated in the first 10-year observation period (RR = 4.9, 95% CI: 1.5, 16.4), whereas the highest increase for non-Hodgkin's lymphoma (RR = 2.8, 95% CI: 1.1, 7.0) and myeloid leukemia (RR = 3.8, 95% CI: 1.2, 12.5) occurred after 15 years. No soft tissue sarcoma cases were found in these zones (0.8 expected). An overall increase in diabetes was reported, notably among women (RR = 2.4, 95% CI: 1.2, 4.6). Chronic circulatory and respiratory diseases were moderately increased, suggesting a link with accident-related stressors and chemical exposure. Results support evaluation of dioxin as carcinogenic to humans and corroborate the hypotheses of its association with other health outcomes, including cardiovascular- and endocrine-related effects.

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. 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. 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.