The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133 ؉ , epithelial-

The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1-2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥ 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management.circulating biomarkers | risk prediction | miRNA ratios D espite recent advances in the management of resected lung cancer and the use of molecular targeted agents in specific clinical settings, the cure rate of non-small-cell lung cancer (NSCLC) remains low due to drug-refractory recurrent and metastatic disease.Early detection studies using chest X-rays (1) and, more recently, spiral-computed tomography (CT; refs. 2 and 3), have reported a significant increase in the number of lung cancer diagnoses, without apparent major decrease in advanced cancers or reduction of mortality in smokers (4). A recent press release (http://www.cancer.gov) reporting the findings of the largest randomized trial comparing spiral-CT to chest X-rays showed a 6.9% reduction in all-cause mortality (−20.3% lung cancer mortality), but a full report of the results of this trial is not yet available. A likely explanation of the limited impact of CT screening on mortality is that perhaps not all aggressive lung tumors arise from identifiable slow-growing precursors, suggesting a possible paradigm shift in our understanding of the natural history of lung cancer (5, 6). In this respect, the identification of biologic and molecular features of indolent and aggressive disease would be critical to define clinically useful predictors of high-risk lesions. microRNAs (miRNAs) are small RNA molecules with regulatory function and marked tissue specificity that can modulate multiple targets belonging to several pathways. They are fr...

We assessed the prevalence of interstitial lung disease (ILD) in a cohort of smokers included in a lung cancer screening trial.Two observers independently reviewed, for the presence of findings consistent with ILD, the computed tomography (CT) examinations of 692 heavy smokers recruited by the Multicentric Italian Lung Detection (MILD) trial. Four CT patterns were considered: usual interstitial pneumonia (UIP), other chronic interstitial pneumonia (OCIP), respiratory bronchiolitis (RB) and indeterminate. Subsequently, the evolution of ILD in those subjects who had undergone a repeat CT examination after 3 yrs was assessed.The UIP pattern and the OCIP pattern were identified in two (0.3%) out of 692 and 26 (3.8%) out of 692 patients, respectively; 109 (15.7%) out of 692 patients showed CT abnormalities consistent with RB, while an indeterminate CT pattern was reported in 21 out of 692 (3%) patients. Age, male sex and current smoking status were factors associated with the presence of OCIP and UIP (combined) pattern, although the relationship did not attain statistical significance. A progression of the disease was observed in three (25%) out of 12 subjects with OCIP who underwent repeat CT after 3 yrs.Thin-section CT features of ILD, probably representing smoking-related ILD, are not uncommon in a lung cancer screening population and should not be overlooked.

Purpose: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls. Experimental Design: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit a type 4], CHRNB4 (cholinergic receptor nicotinic h 4), CHRNA3 (cholinergic receptor nicotinic a 3), and CHRNA5 (cholinergic receptor nicotinic a 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3-and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung. Results: Expression analysis of the six candidate genes mapping in the lung cancer risk^associ-ated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n = 467) and healthy controls (n = 739). Analysis of a family-based series of nonsmoker lung cancer cases (n = 80) and healthy sib controls (n = 80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients. Conclusions: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.Three genomewide studies have reported an association between the chromosome 15 region and lung cancer risk and smoking habit (1 -3). The region, spanning 203 kb, contains six genes [IREB2 (iron-responsive element-binding protein 2), LOC123688, PSMA4, CHRNA5 (cholinergic receptor nicotinic a 5), CHRNA3 (cholinergic receptor nicotinic a 3), and CHRNB4 (cholinergic receptor nicotinic h 4)] that might be good candidates for lung cancer risk. Three of the genes (CHRNA5, CHRNA3, and CHRNB4) encode nicotinic cholinergic receptor subunits, whose biological function may underlie the association with smoking habit. PSMA4 encodes a T1A peptidase family member that is a subunit of the proteasome, whereas IREB2 encodes an iron-responsive element-binding protein; the function of LOC123688 is unknown. The strong linkage disequilibrium in this region has led to the identification of several single-nucleotide polymorphisms showing significant association with lung cancer risk (1 -3). Because small differences in statistical association values cannot serve as the sole basis for distinguishing the relevant functional polymorphism(s) from a single...