DNA methylation is important for gene expression and genome stability, and its disruption is thought to play a key role in the initiation and progression of cancer and other diseases. The DLK1-DIO3 cluster has been shown to be imprinted in humans, and some of its components are relevant to diverse pathological processes. The purpose of this study was to assess the methylation patterns of the DLK1-DIO3 cluster in patients with lung cancer to study its relevance in the pathogenesis of this disease. We found a characteristic methylation pattern of this cluster in smoking associated lung cancer, as compared to normal lung tissue. This methylation profile is not patent however in lung cancer of never smokers nor in lung tissue of COPD patients. We found 3 deregulated protein-coding genes at this locus: one was hypermethylated (DIO3) and two were hypomethylated (DLK1 and RTL1). Statistically significant differences were also detected in two different families of SNORDs, two miRNA clusters and four lncRNAs (MEG3, MEG8, MEG9 and LINC00524). These findings were validated using data from the cancer genome atlas (TCGA) database. We have then showed an inverse correlation between DNA methylation and expression levels in 5 randomly selected genes. Several targets of miRNAs included in the DLK1-DIO3 cluster have been experimentally verified as tumor suppressors. All of these results suggest that the dysmethylation of the imprinted DLK1-DIO3 cluster could have a relevant role in the pathogenesis of lung cancer in current and former smokers and may be used for diagnostic and/or therapeutic purposes.

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BackgroundConflicting data exist on the role of pulmonary dendritic cells (DCs) and their maturation in patients with chronic obstructive pulmonary disease (COPD). Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer.Materials and MethodsA total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes—including BDCA1-positive myeloid DCs (mDCs), BDCA3-positive mDCs, and plasmacytoid DCs (pDCs)—and determine their maturation markers (CD40, CD80, CD83, and CD86) in all participants. We also identified follicular DCs (fDCs), Langerhans DCs (LDCs), and pDCs in 42 patients by immunohistochemistry.ResultsCOPD was diagnosed in 43 patients (16 current smokers and 27 former smokers), whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers). The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively). Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects.ConclusionsCigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung.

BackgroundChronic systemic inflammatory syndrome has been implicated in the pathobiology of extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD). We aimed to investigate which cell types within lung tissue are responsible for expressing major acute-phase reactants in COPD patients and disease-free (“resistant”) smokers.MethodsAn observational case–control study was performed to investigate three different cell types in surgical lung samples of COPD patients and resistant smokers via expression of the C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2 and SAA4) genes. Epithelial cells, macrophages and fibroblasts from the lung parenchyma were separated by magnetic microbeads (CD326, CD14 and anti-fibroblast), and gene expression was evaluated by RT-PCR.ResultsThe sample consisted of 74 subjects, including 40 COPD patients and 34 smokers without disease. All three cell types were capable of synthesizing these biomarkers to some extent. In fibroblasts, gene expression analysis of the studied biomarkers demonstrated increased SAA2 and decreased SAA1 in patients with COPD. In epithelial cells, there was a marked increase in CRP, which was not observed in fibroblasts or macrophages. In macrophages, however, gene expression of these markers was decreased in COPD patients compared to controls.ConclusionsThese results provide novel information regarding the gene expression of CRP and SAA in different cell types in the lung parenchyma. This study revealed differences in the expression of these markers according to cell type and disease status and contributes to the identification of cell types that are responsible for the secretion of these molecules.

BACKGROUND.The prognostic significance of the presence of a neuroendocrine marker (synaptophysin, SY) was analyzed in stage I of squamous carcinoma and adenocarcinoma of the lung.METHODS.A multicentric retrospective study was conducted with immunohistochemical staining in a single center of 318 patients resected for squamous carcinoma or adenocarcinoma in pathologic stage I.RESULTS.In all, 162 cases of squamous carcinoma and 156 cases of adenocarcinoma were identified, which included 105 patients in stage IA (50 patients with squamous carcinoma and 55 patients with adenocarcinoma) and 213 in stage IB (112 with squamous carcinoma and 101 with adenocarcinoma). Eighty‐six tumors showed a presence of SY+ (27%). Univariate analysis showed lower survival rates at 5 years for those patients older than 70 years of age compared with those patients younger than 70 years of age (60.35% vs 70.57%; P = .007) and for those patients with SY+ compared with those with SY− (52.48% vs 72.68%; P = .0017). Patients with SY+ tumors showed a higher rate of recurrence than patients with SY− tumors (50% vs 33.6%; P = .008). Multivariate analysis showed that those patients greater that 70 years of age (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.14–2.65) and the presence of SY (HR, 2.15; 95% CI, 1.40–3.30) were significant independent prognostic factors associated with a poor outcome.CONCLUSIONS.Stage I of squamous carcinoma and adenocarcinoma of the lung with SY+ has a poor prognosis, with a higher frequency of recurrence and lower survival rates. Cancer 2007. © 2007 American Cancer Society.

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