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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic and epigenetic alterations are considered to play important roles in lung cancer. Recent studies showed that EGFR and K-RAS mutations exhibited a mutually exclusive pattern in adenocarcinoma of the lung, suggesting the presence of two independent oncogenic pathways. However, it is unknown how epigenetic alterations were involved in lung carcinogenesis mediated by EGFR or K-RAS mutation. In this study, we examined the relationship between genetic and epigenetic alterations in 164 cases of lung adenocarcinoma. Somatic mutations were determined by direct sequence of EGFR exons 18 to 21 and K-RAS codons 12 and 13. Methylation status of p16(INK4a), RASSF1A, APC, RARbeta, and CDH13, frequently methylated in lung cancer, was determined by methylation-specific PCR and the degree of methylation was defined as the methylation index. Multivariate analysis adjusted for age, sex, and smoking dose showed that the probability of having EGFR mutation was significantly lower among those with p16(INK4a) and CDH13 methylation than in those without [p16(INK4a): odds ratio (OR), 0.07; 95% confidence interval (95% CI), 0.02-0.33; CDH13: OR, 0.34; 95% CI, 0.15-0.77] and the methylation index was significantly lower in EGFR mutant cases than in wild type (OR, 0.70; 95% CI, 0.52-0.95). By contrast, K-RAS mutation was significantly higher in p16(INK4a) methylated cases than in unmethylated cases (OR, 4.93; 95% CI, 1.54-15.7) and the methylation index was higher in K-RAS mutant cases than in wild type with marginal significance (OR, 1.46; 95% CI, 0.95-2.25). Our results indicate the differences in the evolvement of epigenetic alterations between the EGFR- and K-RAS-mediated tumorigenesis and suggest the specific interaction of genetic and epigenetic changes in tumorigenesis of lung cancer.
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PMID:Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers. 1645 91

Detection of lung cancer at early stages could potentially increase survival rates. One promising approach is the application of suitable lung cancer-specific biomarkers to specimens obtained by non-invasive methods. Thus far, clinically useful biomarkers that have high sensitivity have proven elusive. Certain genes, which are involved in cellular pathways such as signal transduction, apoptosis, cell to cell communication, cell cycles and cytokine signaling are down-regulated in cancers and may be considered as potential tumor suppressor genes. Aberrant promoter hypermethylation is a major mechanism for silencing tumor suppressor genes in many kinds of human cancers. Using quantitative real time PCR, we tested 11 genes (3-OST-2, RASSF1A, DcR1, DcR2, P16, DAPK, APC, ECAD, HCAD, SOCS1, SOCS3) for levels of methylation within their promoter sequences in non-small cell lung cancers (NSCLC), adjacent non-malignant lung tissues, in peripheral blood mononuclear cells (PBMC) from cancer free patients, in sputum of cancer patients and controls. Of all the 11 genes tested 3-OST-2 showed the highest levels of promoter methylation in tumors combined with lowest levels of promoter methylation in control tissues. 3-OST-2 followed by, RASSF1A showed increased levels of methylation with advanced tumor stage (P<0.05). Thus, quantitative analysis of 3-OST-2 and RASSF1A methylation appears to be a promising biomarker assay for NSCLC and should be further explored in a clinical study. Our preliminary data on the analysis of sputum DNA specimens from cancer patients further support these observations.
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PMID:Application of a methylation gene panel by quantitative PCR for lung cancers. 1664 4

Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. The agent UBEIL has a remarkable effect on cyclin D1. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors affected the expression of cyclin D1. Interestingly, few dietary compounds listed in this review also have effect on APC, cdk inhibitors p21(Waf1/Cip1) and p27. Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins. This review article reveals potential chemoprevention drug targets, which are mainly centered on cell cycle regulatory pathway genes in cancer.
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PMID:Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets. 1716 75

Research on developing molecular diagnostics for hereditary cancers resulted in establishing diagnostic services for familiar polyposis and non-polyposis patients (mutation determination of APC, MYH, STK11, SMAD4, MLH1, MSH2). In familiar testicular cancers the role of gr/gr gene on Y chromosome was identified. Molecular diagnostic tool was established to monitor the progression of follicular lymphoma using Bcl-2/IgH fusion sequences. Molecular diagnostic tools were developed to monitor circulating endothelial precursor cells (CEP) as well and the technique was tested in lung cancer patients. In malignant melanoma we have tested several potential novel markers among which ryanodine receptor seems to be a promising one, while the functional P2X7 receptor may serve as a therapeutic target. We have determined the tyrosine kinase "kinome" profile of HER-2-amplified breast cancers. Furthermore, the "kinome" profile was found to be characteristic for head and neck cancers of various anatomical location. Based on previous studies on the anti-migratory and antimetastatic potential of low-molecular-weight heparins, we have identified short heparin-derived oligosaccharides with maintained antimetastatic- but non-anticoagulant potentials. Pharmacogenomic studies on the role of polymorphism of the serine-hydroxymethyl-transferase (SHMT) gene in the efficacy of 5-FU and FOLFIRI protocols of colorectal cancer patients revealed a significant effect resulting in altered overall survival as well.
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PMID:[Developments in cancer management by innovative genomics. 2006 report of the National Cancer Consortium]. 1721 11

We previously demonstrated a dominant IgG response against XAGE-1b antigen in a lung cancer patient by serological analysis of antigens by recombinant expression cloning (SEREX) analysis using a cDNA library from the autologous OU-LU-6 tumor cell line. In this study, we investigated recognition of XAGE-1b on OU-LU-6 tumor by the patient CD4-expressing tumor-infiltrating lymphocytes (CD4 TIL). The response of CD4 TIL obtained from malignant pleural effusion was determined against autologous OU-LU-6 tumor cells and XAGE-1b mRNA-transfected PHA-stimulated CD4 T-cells (T-APC) from healthy individuals sharing HLA-DR with the patient by performing IFNgamma secretion and ELISPOT assays. The patient CD4 TIL recognized OU-LU-6 in an HLA-DR-restricted manner and XAGE-1b mRNA-transfected T-APC derived from DRB1 *0901-sharing healthy donor (HD)1 and HD2, but not DRB1 *1101-sharing HD3 or HD4. Epitope analysis using 17 18-mer peptides with 12 overlapping amino acids revealed that the CD4 TIL recognized XAGE-1b 33-49. The findings suggest that the patient CD4 T-cells recognized the XAGE-1b 33-49-related epitope on autologous OU-LU-6 tumor cells in a manner restricted by DR *0901.
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PMID:Identification of DR9-restricted XAGE antigen on lung adenocarcinoma recognized by autologous CD4 T-cells. 1733 21

We performed this study to investigate the aberrant methylation profile of the cancer-related genes in Korean non-small cell lung cancer (NSCLC) that previously exhibited high frequencies of methylation in Western populations. The aberrant promoter methylation of eight genes (GSTP1, p16, FHIT, APC, RASSF1A, hMLH1, hMSH2, AGT) was determined by MSP in 99 surgically resected NSCLCs and their corresponding nonmalignant lung tissues. Methylation in the tumor samples was detected at 15% for GSTP1, 22% for p16, 34% for FHIT1, 48% for APC, 40% for RASSF1A, 18% for hMLH1, 8% for hMSH2 and 21% for AGT, whereas it occurred at lower frequencies in the corresponding nonmalignant lung tissues, particularly in the p16 (1%) and RASSF1A (1%) genes. These results suggest that the methylation profiles of NSCLCs in a Korean population are similar to those in Western populations.
Lung Cancer 2007 Oct
PMID:Aberrant DNA methylation profiles of non-small cell lung cancers in a Korean population. 1753 92

Aberrant promoter methylation represents a main mechanism of tumor suppressor gene inactivation and may serve as a new source for biomarker discovery. This study investigated its applicability as a molecular tool for lung cancer diagnostics on bronchial aspirates. A methylation assay was developed applying a quantitative methylation specific real-time PCR (QMSP). A total of 552 patients with the differential diagnosis of lung cancer were investigated. The QMSP findings on bronchial aspirates were compared with the methylation status of respective genes investigated in microdissected tumor tissues (QMSP, cloning and sequencing of promoter regions after bisulfite conversion). Among the genes tested a marker panel consisting of APC, p16(INK4a) and RASSF1A proved to be the best suited for lung cancer diagnostics. This panel allowed for a correct diagnosis of lung cancer in cases with an ambiguous or false negative conventional cytology. In a cohort study on 247 patients, the combination of histology (sensitivity 59 %), cytology (sensitivity 44 %) and QMSP-assay (sensitivity 53 %) raised the sensitivity of a single bronchoscopy for the diagnosis of lung cancer up to 81%. The methylation assay yielded its major diagnostic surplus with respect to peripheral tumors representing 59 % of all primaries detected. In patients without antecedent lung cancer its specificity considering malignancy was >99 %. Therefore, the QMSP-assay is a promising technique which could enhance the sensitivity and diagnostic impact of conventional cytology. The assay is applicable to residual material of regular diagnostic cytology even in retrospect.
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PMID:[Aberrant promoter methylation as biomarker for molecular cytological diagnosis of lung cancer]. 1786

The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers and genetic alterations. We analyzed markers of DNA damage response (DDR), proliferative stress, and telomeric stress: gamma-H2AX, p16, p53, and TERT. Lung cancer-related epigenetic and genetic alterations, including promoter hypermethylation status of p16(CDKN2A), APC, CDH13, Rassf1, and Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, and c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase and p53 induction. p16 was also induced in early tumorigenic progression and was inactivated in bronchiolar dysplasias and tumors. Remarkably, lack of mutations of Ras and epidermal growth factor receptor, and a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A), CDH13, and APC, but not in Rassf1 and Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer.
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PMID:Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway. 1797 4

A patient exposed to agent orange and a gunshot wound during the Vietnam War has developed multiple medical problems including nocardiosis, onychomycosis (Trichophyton rubrum), multiple thromboembolic episodes, hemochromatosis, diabetes mellitus type 2, diabetic neuropathy, activated protein C resistance (without Leyden V 1st mutation), degree A-V block, lung cancer (metastatic adenocarcinoma), carpal tunnel syndrome and arthritis.
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PMID:Multiple medical problems following agent orange exposure. 1808 83

Previous findings have suggested that methylation of the APC gene may be associated with some tumors including lung cancer. To explore the pattern of APC methylation and the effect of APC gene methylation on its protein expression in lung cancer cell lines, we investigated APC promotor methylation by methylation specific PCR (MSP) and bisulfite sequencing and analyzed the APC protein levels by western blot in three lung cancer cell lines. Monoallelic methylation and 20 methylated CpGs in CpG island near the open reading frame (ORF) of the APC gene were found in the NCI-H460 cell line, and were stablely inherited within 10 generations of the cell line in culture. Our results showed that two special CpG sites (794, 797) might be binding sites for proteins that regulate APC expression. Protein expression of the APC gene in the NCI-H460 cell line declined, but was enhanced after the treatment with 5-aza-2-deoxycytidine (5-aza-dC). Inherited monoallelic methylation of the APC gene may play an important role in lung cancer. Demethylation of the APC gene by 5-aza-dC may be useful for the treatment of lung cancer.
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PMID:The property of methylated APC gene promotor and its influence on lung cancer cell line. 1899 77


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