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

We have developed a rapid and highly sensitive method for the detection of mutant K-ras codon 12 allele in the presence of 10(5) copies of the wild-type alleles. This sensitivity is achieved by selective amplification of mutant K-ras sequences, using a two-stage procedure with modified primers. In the first stage, primers consist of K-ras sequences in the 3' portion and polyomavirus sequence (to minimize homology with human genome) on the 5' portion. The 3' portion also consists of mismatch sequence that generates an MvaI site in normal, but not mutant, K-ras codon 12 alleles. Thus, following the first round of 20 cycles, restriction enzyme cleavage is carried out to selectively digest normal K-ras codon 12 alleles. To enrich mutant alleles, a second amplification is performed using tail primers that recognize the polyoma, but not human sequences. This design ensures that in the second amplification only mutant alleles that were pre-amplified in the first round would serve as template for this reaction. Ethidium bromide-stained polyacrylamide gel electrophoresis (PAGE) of second-stage PCR product that has been digested with MvaI is used to monitor the presence of mutant alleles, detected at sensitivity of 1/10(5). This technique offers high sensitive detection of mutant K-ras alleles using a new concept of tail-primer design and is likely to assist in identifying patients at risk to develop pancreatic, colon, or lung cancer, which harbor high incidence of mutant ras alleles.
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PMID:Quantitative enriched PCR (QEPCR), a highly sensitive method for detection of K-ras oncogene mutation. 933 87

Disease stage is the most important factor in determining prognosis and treatment of lung cancer. Staging of lung cancer is complicated by presentation of multiple pulmonary malignant lesions with a similar histology. It is a dilemma to decide if these lesions are synchronous primaries arising from different malignant clones or metastases from a single clone. Lung cancer is associated with multiple genetic abnormalities including mutations of K-ras and p53, which are believed to occur prior to onset of metastasis. To determine the clonal origin of multiple pulmonary malginant nodules, we analyzed point-mutations of K-ras and p53 by microdissection, polymerase chain reactions (PCR), nonradioisotopic single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. Each pulmonary lesion was microdissected from paraffin slides. Genomic DNA was amplified by two sequential PCRs followed by electrophoresis in a minigel and silver staining. Deoxyribonucleic acid sequencing was performed if necessary to confirm a mutation found upon SSCP analysis. Applying this molecular approach, we were able to differentiate the clonal origins of multiple malignant nodules of the lung as exemplified by the two cases presented.
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PMID:Clonal origin of multiple lung cancers: K-ras and p53 mutations determined by nonradioisotopic single-strand conformation polymorphism analysis. 936 Aug 38

Circulating tumour DNA has previously been detected in serum and plasma of patients with lung cancer and head and neck cancer. These observations could potentially lead to new, specific and non-invasive tools for diagnosis, prognosis and follow-up in neoplastic disease, if found to be a more general phenomenon. To test if tumour DNA is also present in serum of patients with colorectal cancer, we selected 14 colorectal cancer patients with advanced disease. In seven patients, K-ras mutations were detected in the primary tumour, using mutant-specific primers for point mutations in codon 12 or 13 of the K-ras gene. All patients were analysed for mutant DNA in serum. Tumour-specific point mutations, corresponding to the K-ras mutations found in the primary tumour were detected in the serum of all patients but one. No mutant K-ras could be detected in the serum of seven patients without K-ras mutations in the primary tumour. These results may be useful in assessing tumour burden in patients with neoplastic disease. Moreover, consecutive testing of serum tumour DNA after surgery or chemotherapy may be used as a tumour marker for recurrent disease.
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PMID:Detection of tumour DNA in serum of colorectal cancer patients. 939 91

The recent progress in molecular biology has led to the elucidation of pathogenesis of lung cancer. The development of a lung cancer requires multiple genetic changes, consisting of the activation of oncogenes, including the K-ras and myc genes, and of inactivation of tumour suppressor genes, including the Rb, p53 and CDKN2 genes. Knowing the specific genes undergoing such changes should be useful as biomarkers for the early detection of cells destined to become malignant. Moreover, such genetic changes could be targets of newly designed drugs and gene-based therapy. Although the angiotensin I-converting enzyme was originally discovered in equine plasma, it has been recognized in various organs and cells other than vascular endothelial cells. This enzyme is also known to have wide substrate specificity to many peptides. The definite roles of angiotensin converting enzyme (ACE) in the respiratory system are largely unknown. Recent progress in molecular biology of the ACE, however, gives us a good chance to look over the significance of ACE in respiratory diseases as well as cardiovascular disorders. In this review, we show the recent advances in the basic studies of the ACE and refer to its clinical application.
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PMID:Genetic factors in lung disease. Part II: Lung cancer and angiotensin converting enzyme gene. 944 Nov 31

RFLP-mediated PCR has been successfully applied as a reliable tool in the detection of ras mutations in many cancers and provides a basis for "mutant-enriched PCR" protocols. We have, therefore, modified this technique to the sensitive detection of K-ras codon 12 and also p53 "hot spot" mutations, which, frequently in lung cancer, affect codons at the positions 157, 175, 245, 248, 249, and 273. With a high sensitivity of 1 mutant allele in 10(4) normal alleles, our enrichment assay allows the detection of oncogene alleles when only a few tumor cells are present within a normal cell population. Brush cytology material obtained from the tumor site of 20 patients with endoscopically apparent bronchial carcinoma was compared to macroscopically normal mucosa taken from the contralateral bronchus ("control" cytology). We found K-ras codon 12 mutations in 5 cases (25%) and p53 mutations in 13 cases (65%) in the tumor-derived cell material but, with the exception of two cases, not in cell material taken from the control cytology. Seventy-five % of the samples analyzed showed that at least one of the two oncogenes was affected. In several cases, two p53 lesions were detected concomitantly. The majority of the mutations could be reconfirmed by an alternative approach exploiting changes in the genomic RFLP pattern induced by these mutations and were also demonstrated in separate diagnostic biopsies taken. Thus, we conclude that the established enriched PCR protocol ensures a high sensitivity and preserved specificity for the diagnosis of oncogene lesions associated with lung cancer. Because conventional techniques normally yield a lower incidence of corresponding ras and p53 mutations, we think that both the high rate and the heterogeneity of p53 mutations found in some cases are, indeed, related to the increased sensitivity of this new enriched PCR technique.
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PMID:Frequent detection of ras and p53 mutations in brush cytology samples from lung cancer patients by a restriction fragment length polymorphism-based "enriched PCR" technique. 951 24

Patients with non-small-cell lung cancer (NSCLC) survive for variable lengths of time, even when adjustment is made for pathological stage. Numerous reports suggest that biological markers predict survival in patients undergoing surgery for NSCLC with curative intent, but many of these claims are unconfirmed or conflicting. We postulated that the use of multiple putative markers might provide greater power in predicting survival. We studied 101 consecutive patients with NSCLC who underwent exploratory thoracotomy and who were followed for at least 2 yr. We assessed mutations in the p53 tumor suppressor gene (exons 5-8) and the K-ras oncogene (codons 12 and 13) by polymerase chain reaction amplification and single strand conformation polymorphism of the product. We identified 19 K-ras mutations (all adenocarcinomas except for two) and 40 p53 mutations among the 101 cases. We also evaluated p53 protein, bcl-2 protein, c-erbB-1 protein, c-erbB-2 protein, and MIA-15-5 antigen by standard immunocytochemical techniques, and we found that all of these antigens were variably expressed. As expected, we found a strong inverse association between surgical tumor stage and survival. Of the molecular markers studied, only MIA-15-5 antigen expression correlated strongly with survival by univariate analysis (p = 0.001) and it remained a significant predictor by multivariate analysis (p = 0.01). However, in this study, overexpression of MIA-15-5 antigen predicted an improved survival, whereas the original report showed a worse prognosis (N. Engl. J. Med. 1992;327:14). We conclude the multiple cell markers are not clinically useful in predicting survival among patients undergoing surgery for NSCLC. Differences between our results and prior reports may be due to chance, to true population differences, or to other factors.
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PMID:Do molecular markers predict survival in non-small-cell lung cancer? 956 24

Specific genetic alterations affecting known tumor suppressor genes and proto-oncogenes occur during mouse lung tumorigenesis. These include mutational activation of the K-ras gene, commonly seen at a frequency of about 80% in both spontaneously occurring and chemically induced adenomas and adenocarcinomas of the lung, suggesting that it is an early event that persists into malignancy. Allelic loss of the p16 tumor suppressor gene also is a frequent event, occurring in about 50% of mouse lung adenocarcinomas, but rarely in lung adenomas, suggesting that it may play a role in malignant conversion or progression of lung tumors. Other genetic alterations detected in mouse lung tumors include reduced expression of Rb and p16, and increased c-myc expression. Alterations of these genes are also common in the genesis of human lung cancer. Genetic linkage analysis to identify human lung cancer susceptibility genes is difficult due to the genetic heterogeneity and exposure to environmental risk factors. The mouse lung tumor model has become a valuable alternative for identifying such genes. Recently, loci responsible for mouse lung tumor susceptibility have been mapped to chromosomes 6, 9, 17, and 19, while those linked to lung tumor resistance have been mapped to chromosomes 4, 11, 12, and 18. Known candidate susceptibility or resistance genes include the K-ras proto-oncogene on chromosome 6, and the p16 tumor suppressor gene on chromosome 4. With evidence of considerable overlap between the genetic alterations that underlie human and mouse lung tumorigenesis, the mouse lung tumor model has been expanded to include pre-clinical screening of chemopreventive agents against human lung cancer. Studies on the modulation of genetic defects in mouse lung tumors by known and potential chemopreventive agents should further the goal of developing an effective prevention and treatment of lung cancer.
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PMID:Genetic alterations in mouse lung tumors: implications for cancer chemoprevention. 958 49

Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathological features, being prevalently adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinomas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C --> T:A transversions, whereas frameshift mutations and G:C --> A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C --> T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity involving a co-alteration of the p53 gene and the FHIT locus in 20% of cases.
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PMID:Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity at the FHIT locus. 966 54

Cyclin-dependent kinase (CDK) inhibitor genes have recently been proposed as new tumor suppressor genes. To define the possible participation of CDK inhibitor genes in lung carcinogenesis, we investigated the alterations of p15INK4B, p16INK4A, p21Waf1, and p27Kip1 genes in 34 human lung cancer cell lines using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing, and southern dot blot methods. Among the four CDK inhibitor genes, alterations of only the p16INK4A gene were found in 8 out of 34 (24%) cell lines, and all eight cell lines having a p16INK4A gene alteration had an alteration of either the K-ras of p53 gene. Conversely, p16INK4A gene alterations were found in none of the 3 cell lines having Rb gene alterations and none of the 3 cell lines having amplification of the N-myc gene. Polymorphism was found in both p21Waf1 and p27Kip1 genes, but no association was found between the polymorphism and alterations of other genes. These results suggest that p16INK4A gene alterations may play a certain role for lung carcinogenesis in co-operation with either K-ras or p53 gene alterations.
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PMID:Coincidental alterations of p16INK4A/CDKN2 and other genes in human lung cancer cell lines. 967 67

Vascular endothelial growth factor (VEGF) expression and mutations of cancer-related genes increase with cancer progression. This correlation suggests the hypothesis that oncogenes and tumour suppressors regulate VEGF, and a significant correlation between p53 alteration and increased VEGF expression in human lung cancer was reported recently. To further examine this hypothesis, we analysed VEGF protein expression and mutations in p53 and K-ras in 27 non-small-cell lung cancers (NSCLC): 16 squamous cell, six adenocarcinomas, one large cell, two carcinoids and two undifferentiated tumours. VEGF was expressed in 50% of the squamous cell carcinomas (SCC) and carcinoids but none of the others. p53 mutations occurred in 14 tumours (52%), and K-ras mutations were found in two adenocarcinomas and one SCC; there was no correlation between the mutations and VEGF expression. As nitric oxide also regulates angiogenesis, we examined NOS expression in NSCLC. The Ca2+-dependent NOS activity, which indicates NOS1 and NOS3 expression, was significantly reduced in lung carcinomas compared with adjacent non-tumour tissue (P < 0.004). Although the Ca2+-independent NOS activity, which indicates NOS2 expression, was low or undetectable in non-tumour tissues and most carcinomas, significant activity occurred in three SCC. In summary, our data do not show a direct regulation of VEGF by p53 in NSCLC. Finally, we did not find the up-regulation of NOS isoforms during NSCLC progression that has been suggested for gynaecological and breast cancers.
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PMID:Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. 968 99


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