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In eukaryotic cells, DNA is packaged into chromatin and this compact storage in the nucleus promotes transcriptional repression of genes. Chromatin remodeling complexes such as the SWI/SNF complex are involved in making DNA accessible to transcription factors and thereby are implicated in the regulation of gene expression. Mutations and altered expression of chromatin remodeling complex genes have been described in cancer cells. Indeed, non-small cell lung cancer cell lines have been shown to harbor mutations in SMARCA4 (BRG1), a member of the SWI/SNF complex, but evidence has been less clear in primary tumors. Recently, inactivating mutations in AT-rich interaction domain 2 (ARID2) were found in liver cancer related to HCV infection and in melanoma. Here, we explored, using a genome-wide strategy and subsequent sequencing of targeted genes, whether chromatin remodeling is implicated in primary lung adenocarcinoma. Two genes were individualized from the genome screening as homozygously deleted in a set of samples: JARID2 and ARID2. Subsequent analysis of the entire coding sequences showed that ARID2 loss-of-function mutations were found in 5% of nonsmall cell lung cancers, thereby constituting one of the most frequently mutated genes in this cancer type after TP53, KRAS, EGFR, CDKN2A and STK11., (Copyright © 2012 UICC.)

Nonsmall cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths in the United States. We are developing cell-based vaccines as a new approach for the treatment of NSCLC. NSCLC is broadly divided into 3 histologic subtypes: adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Since these subtypes are derived from the same progenitor cells, we hypothesized that they share common tumor antigens, and vaccines that induce immune reactivity against 1 subtype may also induce immunity against other subtypes. Our vaccine strategy has focused on activating tumor-specific CD4(+) T cells, a population of lymphocytes that facilitates the optimal activation of effector and memory cytotoxic CD8(+) T cells. We now report that our NSCLC MHC II vaccines prepared from adeno, squamous or large cell carcinomas each activate CD4(+) T cells that cross-react with the other NSCLC subtypes and do not react with HLA-DR-matched normal lung fibroblasts or other HLA-DR-matched nonlung tumor cells. Using MHC II NSCLC vaccines expressing the DR1, DR4, DR7 or DR15 alleles, we also demonstrate that antigens shared among the different subtypes are presented by multiple HLA-DR alleles. Therefore, MHC II NSCLC vaccines expressing a single HLA-DR allele activate NSCLC-specific CD4(+) T cells that react with the 3 major classes of NSCLC, and the antigens recognized by the activated T cells are presented by several common HLA-DR alleles, suggesting that the MHC II NSCLC vaccines are potential immunotherapeutics for a range of NSCLC patients.

Mutations of the epidermal growth factor receptor gene (EGFR) have been reported to be present in a considerable fraction of lung adenocarcinomas showing dramatic response to EGFR tyrosine kinase inhibitors. To clarify pathogenic significance of the mutations for the development of lung adenocarcinoma, we investigated stage I lung adenocarcinomas for the mutations. First, 107 cases of macrodissected stage I adenocarcinomas were examined for mutations in exons 18-21 of the EGFR gene. EGFR mutations were detected in 36 of the 107 cases (34%). In particular, among the stage I cases, the mutations were detected in 17 of 42 small-sized adenocarcinomas (

Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K-ras and H-ras gene mutations. The occurrence of TP53, p14(ARF) and p16(INK4a) deregulation and H-ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H-ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14(ARF) alterations accounted for 88% and the evidence of p16(INK4a) alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C-->A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14(ARF)and p16(INK4a) promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust-exposed tumors with p16(INK4a) alterations shared TP53 or p14(ARF) deregulation. The present results show a close association of this occupational tumor with TP53, p14(ARF) and p16(INK4a) gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments., (Copyright 2003 Wiley-Liss, Inc.)

The A549 tumor-cell line, initiated from a human alveolar cell carcinoma, has been continuously propagated in vitro for more than 3 years (more than 1,000 cell generations). These cells have a human karyotype and appear to have been derived from a single parent cell. All A549 cells examined by electron microscopy at both early and late passage levels contain multilamellar cytoplasmic inclusion bodies typical of those found in type II alveolar epithelial cells of the lung. At early and late passage levels, the cells synthesize lecithin with a high percentage of disaturated fatty acids utilizing the cytidine diphosphocholine pathway; such a pattern of phospholipid synthesis is expected for cells believed to be responsible for pulmonary surfactant synthesis. The A549 cell line should permit in vitro analysis of human surfactant synthesis and secretion and possibly provide a source of human surfactant for therapeutic intervention in pulmonary disease states characterized by surfactant deficiency.