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

Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one-month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tumorigenesis provides direct estimates of tumor ages, with up to thousands of cell divisions and high death rates necessary to yield the observed diversities. MS molecular tumor clocks have the unique potential to systematically reconstruct the early and occult evolution of individual human mutator phenotype tumors.
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PMID:Somatic microsatellite mutations as molecular tumor clocks. 864 May 59

Genomic imprinting at 11p15 is suggested to play a role in certain pediatric tumors such as Wilms' tumor, based on the findings of selective maternal loss of this chromosomal region. Although the allele loss at 11p15 is also frequent in a number of cancers of adults including lung, breast, and bladder cancers, possible involvement of genomic imprinting in these tumors has not been investigated extensively. p57KIP2, a newly described member of the p21 cyclin-dependent kinase (CDK) inhibitor family which is thought to negatively regulate the cell cycle at the G1 checkpoint, has been mapped to 11p15. In the present study, we searched for somatic p57KIP2 mutations in lung cancer, but failed to find such alterations. Interestingly, however, we found that the p57KIP2 gene is imprinted with maternal expression and that the maternal alleles had been selectively lost in 11 of 13 (85%) lung cancer cases carrying 11p15 deletions, this being a significant bias (p=0.01). These data provide the first evidence that genomic imprinting may play a role in the oncogenesis of not only rare pediatric tumors but also this common cancer of adults, suggesting that the imprinted p57KIP2 CDK inhibitor gene is a potential target for maternally biased 11p15 deletions.
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PMID:Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5. 864 40

Polygenic inheritance of predisposition to cancer is demonstrated in experimental animals for different tumor types. Genetic susceptibility to hepatocarcinogenesis, lung tumorigenesis, skin and intestine carcinogenesis, and plasmacytomagenesis is determined by inheritance of multiple cancer predisposition and resistance alleles, whose chromosomal locations have been found by genetic linkage analysis. In some of these experimental models, genetic heterogeneity has also been reported. In humans, increased risk of lung cancer associated with multiple genes coding for drug metabolizing enzymes, increased risk of cancer in relatives of cancer patients, and genetic heterogeneity are compatible with polygenic inheritance of cancer predisposition. Polygenic inheritance based on the combination of multiple alleles that give predisposition and resistance to cancer would predict a very high risk of cancer in carrier individuals and a marginal increase in the relative risk of cancer in the progeny of the cancer patients. Therefore, predisposition to cancer may be genetically determined even in the absence of familial clustering of cases.
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PMID:A polygenic model of inherited predisposition to cancer. 866 63

This article reviews recent advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the presently available data provide a reasonably clear picture of NNK bioactivation in rodents, although there are still important gaps in our mechanistic understanding of NNK-induced tumorigenesis. The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention.
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PMID:Recent studies on mechanisms of bioactivation and detoxification of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen. 868 59

We have cloned and characterized a putative protein serine/threonine kinase termed prk through a combination of polymerase chain reaction and conventional cDNA library screening approaches. There are apparently two distinct domains within prk protein deduced from its nucleotide sequences. The amino-terminal portion has the feature of the catalytic domain of a serine/threonine kinase and shows strong homology to mouse fnk and other polo family kinases including mouse snk, human and murine plk, Drosophila polo, and yeast Cdc5. The carboxyl-terminal portion, presumably the regulatory domain, shares extensive homology to mouse fnk. Northern blotting analyses reveal that prk expression is restricted to a very limited number of tissues with placenta, ovaries, and lung containing detectable amounts of prk mRNA. prk mRNA expression is also detected at a low level in the megakaryocytic cell line Dami, MO7e, and three brain glioma cell lines. In addition, refeeding of serum-deprived MO7e, Dami, and K562 cells of hematopoietic origin and GMOO637D of lung fibroblasts rapidly activates prk mRNA expression with its peak induction around 2 h after serum addition. prk gene activation by the serum requires no new protein synthesis. The recombinant cytokines such as interleukin-3 and thrombopoietin also activate prk mRNA expression in MO7e cells. Furthermore, a survey of RNAs isolated from the tumor and the uninvolved tissues from 18 lung cancer patients reveals that prk mRNA expression is significantly down-regulated in tumor tissues. Southern blotting analysis indicates that the prk gene is present in a single copy in the genome of tumors and normal cells. Taken together, these results suggest that prk expression may be restricted to proliferating cells and involved in the regulation of cell cycle progression. The molecular cloning of prk cDNA will facilitate the study of its biological role as well as its potential role in tumorigenesis.
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PMID:Prk, a cytokine-inducible human protein serine/threonine kinase whose expression appears to be down-regulated in lung carcinomas. 870 27

It had been thought that the central molecular event in the malignant transformation of a cell is the mutation of certain oncogenes-and the resultant dysregulated activation of their encoded proteins. During the past decade, however, it has become clear that alteration of the activity of the protein products of tumor suppressor genes, through mutation or at the posttranslational level, is an equally basic and universal process in tumorigenesis. These proteins normally modulate cellular proliferation in the developing and adult organism, functioning as tumor suppressors by inhibiting inappropriate cell division. Therefore, inactivation of the normal function of tumor suppressor proteins removes important regulatory constraints on the cell, permitting the accelerated growth of cancerous tissue. The genesis of lung cancer is though to involve between 10 and 20 mutations. Of these, several are now known to involve tumor suppressor genes. In this review I will discuss the mechanism of tumor suppression by the protein encoded by one of these, the retinoblastoma gene, to illustrate precisely why the inactivation of tumor suppressors is a requisite step in cellular progression to lung and other carcinomas.
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PMID:Inactivation of tumor suppressor proteins in lung cancer. 870 70

Cyclin D1, a G1 cyclin, has been implicated in the oncogenesis of various types of malignancies via deregulation of cell cycles. Amplification of cyclin D1 as a part of 11q13 amplicon has been reported in lung cancer as well as a subset of carcinomas arising from various organs including breast, head and neck, and esophagus. In addition to its role as an oncogene, several recent studies have suggested that amplification is indicative of poor prognosis. In this study we examined the cyclin D1 protein expression in 102 consecutive cases of lung cancers using the microwave enhanced immunohistochemical staining method and correlated the data with the histologic subtype and grade, Ki-67 (MIB-1) labeling index, and survival. Nuclear positive staining was observed in 18 cases (18 %) of lung cancers. Although squamous cell carcinoma demonstrated a higher rate of expression (12 /58, 21%), three of 33 adenocarcinomas (9%) revealed overexpression and both adenocarcinoma and squamous cell carcinoma components within the adenosquamous carcinoma showed nuclear staining. There was no correlation between cyclin D1 overexpression and histologic grade, Ki-67 (MIB-1) labeling index, and survival. These observations indicate that cyclin D1 protein overexpression might be implicated in the oncogenesis of the various histologic types of non-small cell lung carcinomas but it has no usefulness as a prognostic marker.
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PMID:Cyclin D1 protein expression in lung cancer. 871 37

Previously we had identified a p53 DNA-binding motif in the 5' region of the CK8 gene This finding led us to study the role of p53 protein in the regulation of CK8 gene expression and its role in tumorigenesis. Human lung cancer cell lines stably transfected with antisense p53 cDNA that expressed little p53 protein were analyzed. CK8 mRNA and the protein expression in these p53 antisense clones were very low as revealed by northern and western blot analysis. Immunofluorescence studies indicated that the cytokeratin networks around the nuclei of these cells collapsed; although some staining was observed around the nuclei. Antisense clones were highly invasive on in vitro matrigel assay. Scanning electron microscopy of the surface topography of these antisense clones revealed a large number of microvilli on their surfaces, a phenotype characteristic of tumor cell invasion. These findings suggest that functional inactivation p53 protein could be an important step in tumor progression.
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PMID:Functional inactivation of p53 by antisense RNA induces invasive ability of lung carcinoma cells and downregulates cytokeratin synthesis. 871 87

Inactivation of the cyclin-dependent kinase inhibitor p16INK4a (CDKN2/MTS1) is documented in a wide variety of cancer cell lines and tumors. We have shown that loss of p16INK4a protein expression is a common event in early stage non-small cell lung cancer (NSCLC), correlates with a significantly worse survival, and is more common in higher stage disease. One hundred NSCLC tumors from patients undergoing definitive thoracotomies at a single institution were examined for p16INK4a and retinoblastoma protein (pRB) expression. Abnormal pRB staining was identified in 15% of the tumors, whereas 51% possessed aberrant p16INK4a protein expression. Tumors with aberrant expression of p16INK4a by immunohistochemistry were associated with a significantly worse survival (P=0.04). Additionally, the inverse correlation of pRB and p16INK4a expression previously noted in lung cancer cell lines and tumors was confirmed in this large cohort of patients, with 65% of the tumors demonstrating inverse expression of pRB and p16INK4a (p=0.00019). A statistically significant increase in aberrant p16INK4a expression, as well as inverse expression of p16INK4a and pRB, was seen with increasing pathological stage of disease. These findings establish the prognostic significance (of the absence of p16INK4, in resected NSCLC and confirm the critical importance of disrupting the pathway of cyclin-dependent kinase-mediated phosphorylation of pRB in the molecular oncogenesis and progression of NSCLC.
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PMID:Rb and p16INK4a expression in resected non-small cell lung tumors. 875 4

In Australia, lung cancer is the most common malignancy in males and the largest cause of cancer deaths. Conventional management has not had a dramatic impact on the mortality rates from lung cancer, which has a case-fatality rate of over 90%. Recent developments in molecular and cellular biology have however, contributed to our knowledge of lung tumorigenesis, which will hopefully translate into clinical benefit for our patients. Many molecular abnormalities are common to both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) but there are differences between these histological types and even within the NSCLC subtypes. This review concentrates on NSCLC, which accounts for up to 85% of Australian lung cancers.
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PMID:Lung pathology: the molecular genetics of non-small cell lung cancer. 877 Nov 43


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