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

Activation of ras oncogenes is commonly found in human neoplasms. We have investigated 280 human lung cancer specimens for ras activation, including 38 that have not been reported previously, using an oligonucleotide detection assay. From a total of 141 adenocarcinoma samples from smokers, 41 tested positive for a point mutation in codon 12 of K-ras (30%), while three tumors had another type of ras activation. Only two of 40 cases from nonsmokers had a K-ras mutation (5%), suggesting that K-ras mutations may be directly caused by exposure to carcinogens in tobacco smoke. The majority of the point mutations in adenocarcinomas were guanine to thymine transversions in codon 12 of the K-ras oncogene. Occasional point mutations in ras oncogenes were detected in adenosquamous carcinomas (one of five cases) and large cell carcinoma (one of 24 cases), but no ras activations were found in small cell carcinomas (six cases), squamous carcinomas (48 cases), carcinoid carcinomas (15 cases), or thymoma (one case). Analysis of the clinical and pathological features of the adenocarcinoma cases showed no apparent associations between the K-ras activation and age at diagnosis, sex, disease stage, and the occurrence of other neoplasms. K-ras-positive adenocarcinomas tended to be less differentiated than the K-ras-negative ones (P = 0.044, chi 2 test for trend). K-ras mutations identify a subgroup of patients with adenocarcinoma of the lung who have a very poor prognosis despite radical resection of their tumor. Although K-ras has been proposed as a target for antitumor therapy, its major clinical significance could be to aid in the selection of patients for specific therapeutic interventions, such as adjuvant chemotherapy.
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PMID:Clinical significance of ras oncogene activation in human lung cancer. 156 97

Small cell lung cancer (SCLC) manifests a number of neuroendocrine differentiation features and antigenic characteristics that distinguish the tumour from non-small cell lung cancer (NSCLC). Several surface antigens on SCLC cells, identified by clusters of monoclonal antibodies (MAbs), distinguish SCLC and other neuroendocrine tumours of NSCLC. Stable transfection of the c-myc proto-oncogene has been reported to confer upon classic SCLC cells the growth properties and morphology of the variant subtype of SCLC (SCLC-v). Furthermore, insertion of the v-Ha-ras oncogene into such SCLC-v cells has been found to induce features typical of NSCLC. We have used classic SCLC cells transfected with c-myc, or co-transformed with c-myc and v-Ha-ras, to examine the expression of characteristics SCLC cluster antigens. Flow cytometric assays reveal that SCLC cells co-transformed with c-myc and v-Ha-ras oncogenes down-modulate SC-1, SC-2 and SC-5A surface antigens to levels approaching, in some cases, those seen with NSCLC cells. The SC-4 surface antigen is not modulated by activation of these oncogenes. These findings support clinical and laboratory observations that important transitions can occur between subtypes of human lung cancer cells, and that these shifts may play a role in the clinical progression of lung cancer.
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PMID:Modulation of neuroendocrine surface antigens in oncogene-activated small cell lung cancer lines. 164 69

The functional properties of Myc proteins are likely to be modulated by interactions with other nuclear proteins. One such protein called Max has already been characterized (1). Through their homologous helix-loop-helix and leucine zipper structures, Myc and Max proteins form heterodimers that bind to specific DNA sequences more efficiently than Myc or Max alone. We have recently identified delta Max, a naturally occurring truncated version of Max, which is also able to dimerize with Myc in the nucleus, but is cytoplasmic in the absence of Myc. These two forms of Max can act either as enhancers or suppressors of cotransformation by c-myc and ras. Oncogenic activation of myc genes in human cancer involves deregulated myc expression. Oncogenes of the myc family are activated in several types of human tumors as a result of gene amplification or chromosomal translocation. We have recently characterized a gene fusion and a chimeric protein product formed by L-myc and part of a novel gene called rlf in small-cell lung cancer (SCLC) cell lines. Although the chimeric mRNAs were shown to be identical, they result from distinct DNA rearrangements. We have also established a physical linkage between normal rlf and L-myc using pulsed field gel electrophoresis. Thus, the rlf-L-myc gene fusions are due to similar but not identical intrachromosomal rearrangements at 1p32. Similar in vivo rearrangements involving rlf and L-myc have been found in at least one primary SCLC tumor. The presence of independent genetic lesions that cause the formation of identical chimeric rlf-L-myc proteins suggests a role for the fusion protein in the development of these SCLC tumors.
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PMID:myc, max, and a novel rlf-L-myc fusion protein in small-cell lung cancer. 166 90

We screened a panel of 103 human lung cancer cell lines for the presence of point mutations at codons 12, 13 or 61 of the human K-, H- and N-ras genes, using restriction fragment length polymorphisms (RFLP), created through mismatched primers during polymerase chain reaction (PCR) of genomic DNA. We found ras mutations in 22/61 (36%) non-small-cell lung cancer (NSCLC) cell lines, predominantly in K-ras codon 12. Identical mutations were present in uncultured tumor materials corresponding to 11 cell lines containing mutated ras genes. ras mutations were found not only in adenocarcinoma cell lines (9/32, 28%), but also in cell lines derived from other types of NSCLC (13/29, 45%). In contrast, none of 37 small-cell lung cancer (SCLC) cell lines and five extra-pulmonary small-cell cancer cell lines had ras mutations. ras mutations were not correlated with sex of the patients, tumor extent, prior therapy status or in vitro culture time. G to T or A to T transversions were the most common base substitutions, occurring in codons 12 and 61 respectively. We conclude that ras mutations play a role in the pathogenesis of a subset of NSCLC but are not involved in SCLC.
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PMID:Mutations of ras genes distinguish a subset of non-small-cell lung cancer cell lines from small-cell lung cancer cell lines. 167 29

Altered and deregulated cellular oncogenes were found in many human solid tumors. Except for a few types of tumors that consistently exhibited specific altered proto-oncogenes, the majority of tumors are associated with a number of transcriptionally activated cellular oncogenes. In the heterologous group of non-small-cell lung cancer (NSCLC), nothing about a specific pattern of proto-oncogene expression is known. Therefore, we investigated the expression of a panel of cellular oncogenes in NSCLC cell lines. DNA and RNA from 11 established NSCLC cell lines (4 adenocarcinoma cell lines, 3 squamous cell carcinoma cell lines, 3 large-cell carcinoma cell lines and 1 mesothelioma cell line) were isolated and analysed using the Southern, dot blot and Northern hybridization technique. c-myc RNA expression was found in all NSCLC cell line, L-myc expression only in 1 adenocarcinoma cell line, N-myc and c-myb expression in none of the 11 cell lines examined. No c-myc amplification could be detected in the DNAs. v-sis-related mRNA was observed in 5/11 cell lines without association to a specific NSCLC subtype. v-src-related mRNA, found in all tested cells, exhibited increased levels in 1 adenocarcinoma cell line (A-549) compared to the other cell lines. Binding sites for epidermal growth factor (EGF) had been described previously in NSCL, therefore we found erbB homologue transcripts coding for the EGF receptor in all NSCLC cell lines. Also, c-raf1-, N-ras-, Ki-ras-, and H-ras-related RNA expression was observed in all lines. We conclude that L-myc, N-myc, and c-myb expression does occur less frequently in NSCLC than in SCLC. Also amplification does not appear to be an important mechanism by which the c-myc proto-oncogene is activated in NSCLC. A specific pattern of oncogene expression could not be detected in NSCLC cells; each cell line examined showed its own pattern. However, transcriptional activation of a proto-oncogene like erbB, ras, raf, src, and c-myc, which are all involved in the progression pathway of EGF, may be a common feature of NSCLC.
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PMID:Different pattern of expression of cellular oncogenes in human non-small-cell lung cancer cell lines. 169 Feb 10

Restriction fragment length polymorphism analyses of the Ha-ras-1 proto-oncogene were undertaken in white and black populations residing in the Baltimore-Washington metropolitan area to address whether specific rare alleles of the Ha-ras-1 proto-oncogene locus vary in their distribution among different racial groups. High-molecular-weight genomic DNA samples from the lungs of 80 lung cancer patients and 92 accident victims were digested with appropriate restriction enzymes and subjected to Southern analysis using the 6.6-kb BamHI human Ha-ras-1 recombinant fragment from the plasmid pEC. Thirty allelomorphs of different sizes were detected among the 172 study subjects. An association was observed between race and specific alleles. Rare alleles were more frequent in black cancer patients and trauma victims than in whites. Within each racial category, lung cancer patients had an excess of rare alleles. These data indicate the importance of controlling for racial variation when designing studies to determine human cancer risk factors.
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PMID:Racial variation in the distribution of Ha-ras-1 alleles. 171 39

Neuroendocrine lung cancers can be induced in hamsters within 8-12 weeks by combined exposure to N-nitrosodiethylamine (DEN) and hyperoxia. The expression of the c-Ki-ras gene in this lung cancer model was studied using polymerase chain reaction analysis of mRNA (RNA/PCR). We used four different groups of hamsters, exposed for 6 weeks to DEN with hyperoxia (60% oxygen), DEN, hyperoxia, or ambient air, respectively. Total RNA was isolated from lung tissues and cDNA made prior to PCR amplification. A 234-bp product was amplified from c-Ki-ras cDNA and quantitated using scanning laser densitometry. The data obtained were normalized to the expression of the house keeping gene B-actin. The c-Ki-ras products were present after amplification of all hamster lung RNA samples. The hamster lungs exposed to DEN with hyperoxia displayed higher c-Ki-ras protooncogene expression than hamsters exposed to DEN, hyperoxia, or ambient air alone. Since the animals studied were sacrificed at 6 weeks, prior to the appearance of tumors, we conclude that this increased expression may indicate a role for c-Ki-ras in the initial steps in malignant transformation of neuroendocrine cells.
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PMID:Increased c-Ki-ras expression in hamster lung exposed to N-nitrosodiethylamine and hyperoxia as detected by the polymerase chain reaction. 171 35

Pulmonary carcinogenesis due to occupational and environmental exposures to chemical carcinogens such as polycyclic aromatic hydrocarbons presents an interesting model for study of possible oncogene-related cancer biomarkers. Polycyclic aromatic hydrocarbons are important respiratory carcinogens and have been shown to cause specific mutational lesions that can lead to the activation of the ras oncogene and expression of its p21 protein product; ras oncogene activation and p21 expression frequently are detected in human lung cancers. In addition, the p21 protein is detectable via immunoblotting techniques in the serum of lung cancer patients and in selected persons in exposed worker cohorts at risk for the development of lung cancer. Thus, the ras oncogene and p21 protein may be useful biomarkers for monitoring pulmonary carcinogenesis in exposed populations.
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PMID:Advances in cancer biomarkers as applied to chemical exposures: the ras oncogene and p21 protein and pulmonary carcinogenesis. 174 43

Lung cancer is a leading cause of cancer-related deaths in several nations. Epidemiological studies have indicated that 85% of all lung cancer deaths and 30% of all cancer deaths in the U.S. are associated with tobacco smoking. Various chemicals in tobacco smoke are thought to react with DNA and to ultimately yield heritable mutations. In an effort to understand the molecular mechanisms involved in lung tumorigenesis, we have analyzed proto-oncogene activation in a series of human lung tumors from smokers and spontaneously occurring and chemically induced lung tumors in mice. Approximately 86% of the human lung tumors and greater than 90% of the mouse lung tumors were found to contain activated oncogenes. ras Oncogenes activated by point mutations were detected in many of the human lung adenocarcinomas and virtually all of the mouse lung adenomas and adenocarcinomas. The mutation profiles of the activated K-ras genes detected in the chemically induced mouse lung tumors suggest that the observed mutations result from genotoxic effects of the chemicals. Comparison of the K-ras mutations observed in the human lung adenocarcinomas with mutation profiles observed in the mouse lung tumors suggest that bulky hydrophobic DNA adducts may be responsible for the majority of the mutations observed in the activated human K-ras genes. Other data indicate that approximately 20% of human lung tumors contain potentially novel transforming genes that may also be targets for mutagens in cigarette smoke.
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PMID:Activation of proto-oncogenes in human and mouse lung tumors. 177 85

The probability that a mouse develops a pulmonary tumor, as well as the structure of that tumor, are dependent on several genes. Three pulmonary adenoma susceptibility (pas) genes predispose some inbred strains to develop lung tumors, even in the absence of carcinogen exposure, and cause others to be resistant. One pas gene is K-ras, which may also be overexpressed in these tumors in a mutated form capable of transforming cells. Mice with activated Ha-ras transgenes override the resistant pas alleles and are born with lung cancer. Susceptible strains have a higher turnover rate of alveolar type II and bronchiolar Clara cells, those cells from which lung tumors arise, than more resistant strains. A high precursor cell turnover rate correlates with a propensity to neoplasia in other animal models as well, possibly due to low concentrations of endogenous growth regulatory molecules such as corticosterone and protein kinase C (PKC). Neoplastic lung epithelial cells are relatively resistant to glucocorticoids and have low PKC levels. A set of genes other than the pas genes governs the response to tumor modulation by butylated hydroxytoluene (BHT). The genes that determine whether lung tumor multiplicity is enhanced by chronic BHT exposure may regulate the ability to hydroxylate BHT at a tert-butyl position to form BHT-OH, a metabolite with greater tumor-promoting potency than BHT. Inbred and recombinant inbred strain variations in adenoma growth patterns indicate that another set of genes, which we have designated pah for pulmonary adenoma histogenesis, may determine which cell type becomes neoplastic and whether adenomas will undergo malignant conversion.
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PMID:Genetic studies on lung tumor susceptibility and histogenesis in mice. 177 86


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