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

Cell lines of non-small cell lung cancer (non-SCLC) have been shown to contain activating mutation of the K-ras oncogene in about 30% of cases, whereas no small cell lung cancer (SCLC) cell lines displayed these mutations. Biochemically, these mutations result in the ras gene product (p21) being constitutively activated in its GTP-bound form and insensitive to the hydrolytic action of the ras-specific GTPase-activating protein (ras GAP). We hypothesized that, if tumor development is related to the p21 ras being in the active GTP-bound state, then a similar malignant phenotype may result from an inactivating mutation in the ras GAP gene in the region that interacts with ras p21 (so-called catalytic domain). To test this hypothesis, we screened a panel of SCLC and non-SCLC cell lines for major genetic alterations in the catalytic domain of the GAP gene with the Southern blot technique, and for minor genetic abnormalities (e.g., point mutations) with denaturing gradient gel electrophoresis and single-strand conformation polymorphism. Mutations in the catalytic domain of the GAP gene could not be demonstrated by any technique in any cell line examined. We conclude that mutational inactivation of the catalytic domain of the GAP gene probably does not contribute to the development of lung cancer.
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PMID:Genetic analysis of the catalytic domain of the GAP gene in human lung cancer cell lines. 827 Feb 51

From 10 to 30% of lung carcinomas examined to date contain mutant K-ras genes. We report here that the mutant-allele-specific amplification (MASA) method may be useful for detection of the K-ras mutations in cells obtained from the sputum of patients with lung cancer. The PCR product from one of five patients revealed an alteration when mixed oligonucleotides representing variants of the second letter at codon 12 of this gene were used as 5' primers, and further experiments showed a mutation of GGT (Gly) to GAT (Asp) at codon 12. The MASA system could also be applied to an examination of metastatic lung carcinomas, particularly from adenocarcinomas in colon and pancreas in which frequent K-ras mutations are detected, and to mass-screening for colorectal tumors using DNA isolated from feces as template.
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PMID:Detection of K-ras mutation in sputum by mutant-allele-specific amplification (MASA). 831 87

Research on dominant oncogenes and tumor suppressor genes has characterized differences in genetic lesions between small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and identified associations with clinical parameters. More than one half of all lung cancers contain a mutation of the p53 tumor suppressor gene. There does not appear to be an association between the presence of this mutation and survival. A ras family oncogene was found to be mutated in approximately 20 percent of tumors and tumor cell lines from patients with NSCLC in contrast to none of 45 tumors and tumor cell lines from patients with SCLC. The presence of a K-ras mutation was determined to be an adverse prognostic factor for survival in retrospective studies of patients with NSCLC. Mutations of K-ras are more common in tumors from smokers than nonsmokers and have not been detected in lung cancers resulting from occupational exposure to radon. Mutations in both the p53 gene and K-ras oncogene are most commonly G to T transversions in lung cancer vs G to A transitions in other cancers. Prospective studies of these mutations in resected tumor specimens taken from patients with accurate follow-up may continue to provide important clues about their potential clinical and biologic significance.
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PMID:Overview of genetic and molecular events in the pathogenesis of lung cancer. 838 Jan 30

A retroviral vector system was developed to transduce a K-ras antisense construct efficiently into human cancer cells. A 2-kb fragment of K-ras gene DNA in antisense orientation was linked to a beta-actin promoter and inserted into retroviral vector LNSX in two different orientations. The constructs were transfected into amphotropic packaging cell line GP+envAm12 followed by alternating transduction between the ecotropic packaging cell line psi-2 and GP+envAm12. Titers up to 9.7 x 10(7) colony-forming units (cfu)/ml were achieved without detectable replication-competent virus. The human large cell lung carcinoma cell line H460a, which has a homozygous codon 61 K-ras mutation, was transduced with an efficiency of 95% after five to seven repeated transductions. DNA polymerase chain reaction (PCR) and genomic DNA Southern blot analysis showed that the retroviral construct was integrated into the genome of H460a cells. K-ras antisense RNA expression was detected in the cells by Northern analysis, slot blot hybridization, and reverse transcriptase-PCR. Translation of the mutated K-ras p21 protein RNA was specifically inhibited, whereas expression of other p21 species was unchanged. Proliferation of H460a cells was suppressed 10-fold following transduction by the antisense construct. Colony formation in soft agarose and tumorigenicity in an orthotopic lung cancer model in nu/nu mice were dramatically reduced in H460a cells expressing antisense K-ras. We conclude that an antisense construct for K-ras can be expressed effectively in a retroviral vector that can efficiently transduce human cancer cells.
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PMID:Retroviral vector-mediated transduction of K-ras antisense RNA into human lung cancer cells inhibits expression of the malignant phenotype. 839 92

We investigated point mutational activation of the ras genes (K-ras codons 12, 13 and 61; N-ras codons 12, 13 and 61; H-ras codons 12 and 61) in primary, resected lung cancer by dot blotting and oligonucleotide hybridization. K-ras mutations were found in 14 (29%) of the 48 lung tumour specimens examined, but no N-ras or H-ras mutations were found. The highest frequency of K-ras mutation was observed in adenocarcinoma: 12 of the 21 samples studied (57%) had a mutation, which is one of the highest frequencies reported for lung adenocarcinoma. The commonest type of mutation in these lung tumour samples consisted of transversions: we observed 11, of which 8 (57% of all mutations) were G to T transversions. Most of the 48 patients studied had a history of heavy smoking, either with or without evidence of occupational exposure to asbestos. Statistical analysis revealed--in addition to the highly significant association between the adenocarcinoma type of lung cancer and K-ras mutation--a clear association of K-ras mutations with heavy life-time smoking (> or = 50 pack-years of cigarette smoking; odds ratio (OR) 4.9, 90% CI 1.2-19.5, multivariate analysis). In addition, occupational asbestos exposure showed an elevated, but non-significant, OR of 2.2 (90% CI 0.6-8.7) with the presence of K-ras mutation. We conclude that the occurrence of K-ras mutations in adenocarcinoma of the lung is frequent, and that such mutations are associated with heavy life-time exposure to tobacco smoke, possibly in combination with occupational exposure to asbestos fibres.
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PMID:K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos. 842 62

An orthotopic human lung cancer model in nu/nu mice was used to study the effect of an antisense K-ras (AS-K-ras) retroviral construct on tumor growth in vivo. A 2-kilobase genomic AS-K-ras DNA fragment linked to a beta-actin promoter was cloned into the LNSX retroviral vector. The recombinant construct was packaged into GP+envAm12 cells and titers greater than 10(6) colony-forming units/ml were obtained. Irradiated (350 cGy) nu/nu mice were first inoculated intratracheally with 10(5) H460a human large cell lung carcinoma cells which have a codon 61 mutation of the K-ras oncogene. Three days later they received intratracheal instillation of viral supernatant (5 x 10(6) colony-forming units/ml) from either LNSX, LNSX-AS-K-ras, LNSX-sense-K-ras producer cells, or medium daily for 3 days. At autopsy, 30 days after tumor cell inoculation, 90% of the control mice had tumors whereas 87% of mice treated with the LNSX-AS-K-ras viral supernatant were free of tumors. The efficacy of the viral supernatant was dose dependent. Intratracheal administration of retroviral LNSX-AS-K-ras supernatant prevents the growth of human lung cancer cells implanted orthotopically in nu/nu mice.
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PMID:Prevention of orthotopic human lung cancer growth by intratracheal instillation of a retroviral antisense K-ras construct. 846 90

Inhalation of high-linear energy transfer radiation in the form of radon progeny is a suspected cause of human lung cancer. To gain insight into the types of genetic derangement(s) caused by this type of radiation, lung tumors from beagle dogs exposed to 239PuO2 and those arising in animals with no known carcinogen exposure were examined for evidence of aberrations in genes known to be altered in lung tumors. Altered expression of the p53 tumor suppressor gene and proto-oncogene erbB-2 proteins (p185erbB2) was evaluated by immunohistochemical analysis of 117 tumors representing different histological types in exposed (n = 80) and unexposed (n = 37) animals. Twenty-eight tumors were analyzed for K-ras proto-oncogene mutations by polymerase chain reaction amplification and direct sequencing. Fourteen percent (16/116) of all lung neoplasms showed elevated nuclear accumulation of p53 protein. Regardless of exposure history, adenosquamous and squamous cell cancers comprised 94% of all tumors with p53 abnormalities. Eighteen percent (21/117) of all tumors had evidence in codons 12, 13 or 61 tumors from unexposed (n = 9) or plutonium-exposed dogs (n = 19). These data indicate that p53 and K-ras gene abnormalities as a result of missense mutation are infrequent events in spontaneous and 239PuO2-induced lung neoplasia in this colony of beagle dogs. Alternative mechanisms of gene alteration may be involved in canine pulmonary carcinogenesis.
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PMID:p53, erbB-2 and K-ras gene alterations are rare in spontaneous and plutonium-239-induced canine lung neoplasia. 860 28

Oncogene and tumor suppressor gene mutations are candidate biomarkers for cancer risk assessment and lesion detection. The K-ras oncogene has previously been associated with non-small cell lung cancer (NSCLC), particularly adenocarcinomas in which reported rates of mutation have approached 30-40%. We have analyzed non-malignant lung tissue from patients with lung cancer and primary lung cancers for K-ras gene mutations. Mutations were detected in 32% cancers and 29% non-malignant lung tissue from patients with cancer. The majority of tumors testing positive were adenocarcinoma of the lung. Normal DNA controls, including peripheral blood lymphocytes and normal lung from non-smokers, were negative. The ability to detect genetic alterations in non-malignant lung tissues is consistent with the concept that genetic alterations are involved in field cancerization of the aerodigestive tract.
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PMID:Detection of K-ras gene mutations in non-neoplastic lung tissue and lung cancers. 861 4

The p53 tumor suppressor gene has been found to be altered in almost all human solid tumors, whereas K-ras gene mutations have been observed in a limited number of human cancers (adenocarcinoma of colon, pancreas, and lung). Studies of mutational inactivation for both genes in the same patient's sample on non-small-cell lung cancer have been limited. In an effort to perform such an analysis, we developed and compared methods (for the mutational detection of p53 and K-ras gene) that represent a modified and universal protocol, in terms of DNA extraction, polymerase chain reaction (PCR) amplification, and nonradioisotopic PCR-single-strand conformation polymorphism (PCR-SSCP) analysis, which is readily applicable to either formalin-fixed, paraffin-embedded tissues or frozen tumor specimens. We applied this method to the evaluation of p53 (exons 5-8) and K-ras (codon 12 and 13) gene mutations in 55 cases of non-small-cell lung cancer. The mutational status in the p53 gene was evaluated by radioisotopic PCR-SSCP and compared with PCR-SSCP utilizing our standardized nonradioisotopic detection system using a single 6-microns tissue section. The mutational patterns observed by PCR-SSCP were subsequently confirmed by PCR-DNA sequencing. The mutational status in the K-ras gene was similarly evaluated by PCR-SSCP, and the specific mutation was confirmed by Southern slot-blot hybridization using 32P-labeled sequence-specific oligonucleotide probes for codons 12 and 13. Mutational changes in K-ras (codon 12) were found in 10 of 55 (18%) of non-small-cell lung cancers. Whereas adenocarcinoma showed K-ras mutation in 33% of the cases at codon 12, only one mutation was found at codon 13. As expected, squamous cell carcinoma samples (25 cases) did not show K-ras mutations. Mutations at exons 5-8 of the p53 gene were documented in 19 of 55 (34.5%) cases. Ten of the 19 mutations were single nucleotide point mutations, leading to amino acid substitution. Six showed insertional mutation, and three showed deletion mutations. Only three samples showed mutations of both K-ras and p53 genes. We conclude that although K-ras and p53 gene mutations are frequent in non-small-cell lung cancer, mutations of both genes in the same patient's samples are not common. We also conclude that this universal nonradioisotopic method is superior to other similar methods and is readily applicable to the rapid screening of large numbers of formalin-fixed, paraffin-embedded or frozen samples for the mutational analysis of multiple genes.
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PMID:A universal method for the mutational analysis of K-ras and p53 gene in non-small-cell lung cancer using formalin-fixed paraffin-embedded tissue. 863 83

Induction (neoadjuvant) chemotherapy has become an accepted treatment for stage IIIA (T1-3N2M0) non-small cell lung cancer. In two recent randomized trials, neoadjuvant chemotherapy plus surgery gave an increase in median survival at least fivefold greater than surgery alone. The Spanish Lung Cancer Group trial of preoperative chemotherapy, in which the cisplatin dose was randomized to either 50 mg/m2 or 100 mg/m2 plus 3 g/m2 ifosfamide and 6 mg/m2 mitomycin, examines the effect of K-ras gene mutations on tumor response and survival. Patients whose tumors contain K-ras gene mutations are more likely to develop distant metastases and have lower median survival than patients without such mutations. Microsatellite instability seems to be a frequent mechanism of genetic aberrations. Knowledge about these genetic alterations could have prognostic importance and may identify the patients who should receive the most aggressive additional treatment.
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PMID:The role of induction (neoadjuvant) chemotherapy in stage IIIA NSCLC. 863 84


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