BackgroundTobacco 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.Methodology/Principal FindingsWe 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.Conclusions/SignificanceOur 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.

No abstract

We consider the problem of detecting features in spatial point processes in the presence of substantial clutter. One example is the detection of mine elds using reconnaissance aircraft images that erroneously identify many objects that are not mines. Another is the detection of seismic faults on the basis of earthquake catalogs: earthquakes tend to be clustered close to the faults, but there are many that are farther away.Our solution uses model-based clustering based on a mixture model for the process, in which features are assumed to generate points according to highly linear multivariate normal densities, and the clutter arises according to a spatial Poisson process. Very nonlinear features are represented by several highly linear multivariate normal densities, giving a piecewise linear representation.The model is estimated in two stages. In the rst stage, hierarchical model-based clustering is used to provide a rst estimate of the features. In the second stage, this clustering is re ned using the EM algorithm. The number of features is found using an approximation to the posterior probability of each n umber of features.For the mine eld problem, this method yields high detection rates and low false positive rates. For the seismic fault problem, the method accurately recovers the documented faults in the San Francisco Bay a r e a .

No abstract