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

N-myc and L-myc proto-oncogenes are expressed in many developing embryonic tissues. In contrast to expression of the closely related c-myc gene, N-myc and L-myc expression is very restricted in adult tissues. We show that small amounts of the L-myc RNA can be detected in normal adult testicular tissue. A high level of N-myc expression from a single-copy N-myc gene was found in a malignant tumor of the testis, histopathologically defined as a seminoma. This tumor also showed a decrease of mRNA from the retinoblastoma gene (RB), which is ubiquitously expressed in all normal tissues. Strikingly similar results on elevated expression of the L-myc and N-myc genes and a lack of RB mRNA have been reported in small-cell lung cancer cell lines, and are confirmed in our study.
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PMID:Oncogene expression in small-cell lung cancer cell lines and a testicular germ-cell tumor: activation of the N-myc gene and decreased RB mRNA. 254 35

We examined Southern blot analyses of normal and tumor DNAs from 50 patients with sporadic renal cancer, using the human L-myc oncogene fragment as a hybridization probe. Our purpose was to study the relationship between the restriction fragment length polymorphism (RFLP) of the L-myc and the frequencies of metastases. There was no individual difference in patterns of L-myc RFLP between normal and tumor-tissue DNAs digested with EcoRI. The patients were classified into 3 genetic types according to the polymorphic patterns defined by the 2 alleles [10-kilobase (kb) and 6.6-kb fragments]. The relative ratios of the 3 genotypes in the renal cancer patients were similar to those seen in healthy Japanese. However, of 16 patients who exhibited distant organ metastases at the time of surgery, only one was a 10-kb fragment homozygote. The incidence of distant metastases in 10-kb homozygotes was significantly lower than that in 6.6-kb homozygotes plus heterozygotes (p = 0.06). These results basically correspond to the previous findings in the lung cancer patients, and suggest that L-myc RFLP is a widely applicable genetic marker to predict prognosis in cancer patients.
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PMID:Restriction fragment length polymorphism of the L-myc gene and susceptibility to metastasis in renal cancer patients. 256 78

We analyzed in detail the structure of the L-myc gene isolated from human placental DNA and characterized its expression in several small-cell lung cancer cell lines. The gene is composed of three exons and two introns spanning 6.6 kilobases in human DNA. Several distinct mRNA species are produced in all small-cell lung cancer cell lines that express L-myc. These transcripts are generated from a single gene by alternative splicing of introns 1 and 2 and by use of alternative polyadenylation signals. In some mRNAs there is a long open reading frame with a predicted translated protein of 364 residues. Amino acid sequence comparison with c-myc and N-myc demonstrated multiple discrete regions with extensive homology. In contrast, other mRNA transcripts, generated by alternative processing, could encode a truncated protein with a novel carboxy-terminal end.
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PMID:Structure and expression of the human L-myc gene reveal a complex pattern of alternative mRNA processing. 282 2

The molecular mechanisms reported to regulate the expression of myc family genes are multiple and complex and include gene amplification, transcriptional activation, transcriptional attenuation, and mRNA stability. We have investigated which of these mechanisms are responsible for the extreme variation in myc gene family mRNA levels observed in human small-cell lung cancer cell lines. In addition to gene amplification, a block to nascent mRNA chain elongation, causing attenuation of transcription, is an important regulatory mechanism controlling the steady-state levels of c-myc and L-myc mRNA. The loss of transcriptional attenuation is correlated with overexpression of these two genes in cell lines which do not show gene amplification. Expression of c-myc mRNA appears to be dependent on promoter activity and attenuator function. In contrast, regulation of expression of the N-myc gene does not involve transcriptional attenuation; steady-state mRNA levels are correlated with promoter activity as well as gene amplification. We conclude that transcriptional regulation of each member of the myc gene family is accomplished by a different assortment of complex mechanisms, including gene copy number, promoter activation, and transcriptional attenuation. Interference at multiple points in this complex regulatory process appears to be an important mechanism by which small-cell lung cancer and other human tumors evade growth control.
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PMID:Multiple mechanisms for transcriptional regulation of the myc gene family in small-cell lung cancer. 285 Apr 89

Altered structure and regulation of the c-myc proto-oncogene have been associated with a variety of human tumours and derivative cell lines, including Burkitt's lymphoma, promyelocytic leukaemia and small cell lung cancer (SCLC). The N-myc gene, first detected by its homology to the second exon of the c-myc gene, is amplified and/or expressed in tumours or cell lines derived from neuroblastoma, retinoblastoma and SCLC. Here we describe a third myc-related gene (L-myc) cloned from SCLC DNA with homology to a small region of both the c-myc and N-myc genes. Human genomic DNA shows an EcoRI restriction fragment length polymorphism (RFLP) of L-myc defined by two alleles (10.0- and 6.6-kilobase (kb) EcoRI fragments), neither associated disproportionately with SCLC. Mouse and hamster DNAs exhibit a 12-kb EcoRI L-myc homologue, which indicates conservation of the gene in mammals. Gene mapping studies assign L-myc to human chromosome region 1p32, a location distinct from that of either c-myc or N-myc but associated with cytogenetic abnormalities in certain human tumours. This L-myc sequence is amplified 10-20-fold in four SCLC cell line DNAs and in one SCLC tumour specimen taken directly from a patient. Either the 10.0- or 6.6-kb allele can be amplified and in heterozygotes only one of the two alleles was amplified in any SCLC genome. SCLC cell lines with amplified L-myc sequences express L-myc-derived transcripts not seen in SCLC with amplified c-myc or N-myc genes. In addition, some SCLCs without amplification also express L-myc-related transcripts. Together, these findings suggest an enlarging role for myc-related genes in human lung cancer and provide evidence for the concept of a myc family of proto-oncogenes.
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PMID:L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. 299 22

c-myc oncogene is the most extensively studied member of the myc gene family, which now consists of three characterized members, namely the c-myc, N-myc, and L-myc genes. Deregulation owing to amplification and/or rearrangements of the c-myc gene have been described in a variety of human malignancies. Several neuroblastomas have amplifications of the N-myc genes. The c-myc, N-myc, or L-myc oncogenes are also found amplified in different cell lines from small cell carcinomas of the lung. In this study, we have examined the c-myc, N-myc, and c-erbB oncogenes in 34 clinical and autopsy tumor specimens representing various histopathological types of human lung cancer, including nine small cell lung cancers. A 30-fold amplification of the N-myc gene was found in a tumor histopathologically and histochemically verified as a typical adenocarcinoma. No amplifications of the c-myc or c-erbB oncogenes were seen in any of the tumors. In the DNA of one small cell carcinoma, an extra c-myc and N-myc cross-hybridizing restriction fragment was observed, possibly owing to an amplification of a yet uncharacterized myc-related gene.
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PMID:Amplification of the N-myc oncogene in an adenocarcinoma of the lung. 302 69

Molecular and cell biologic studies of a large number of lung cancer cell lines of all histologic types have revealed several mechanisms active in the pathogenesis of these cells. Small cell lung cancer (also called "oat cell" lung cancer) has a deletion involving chromosome region 3p(14-23) that is confirmed by DNA restriction fragment length polymorphisms analysis (studies done in collaboration with Dr. Susan Naylor). Several lung cancers of both small cell and non-small cell type (including adeno- and squamous cell lung cancer) express the proto-oncogenes c-, N-, or L-myc, and in some cases more than one of these family members. N-myc appears restricted in its expression to the small cell lung cancer type while c-myc and L-myc can be expressed in both small cell and non-small cell lung cancers. Many lung cancers of all histologic types also express large amounts of p53, which are not correlated with the amount or type of myc gene product expressed. In small cell lung cancer, high levels of myc gene expression are usually associated with gene amplification, and not uncommonly there is rearrangement of some of the amplified copies. In non-small cell lung cancer, expression without amplification or rearrangement of myc genes is seen. In contrast, high level expression of p53 is not associated with gene amplification in any lung cancer type. In addition, to these proto-oncogenes acting at a presumed nuclear locus, there is increased expression of various ras family members and the c-raf-1 proto-oncogene (in collaboration with Dr. Ulf Rapp). Lung cancer cells in tissue culture can grow in medium without serum and few or no other growth factors added. Thus, it appears that lung cancer cells can produce their own growth factors which can act in an "autocrine" fashion. The best characterized example of this is gastrin releasing peptide (GRP, also called bombesin) produced by small cell lung cancer. In at least some small cell lung cancers, interference with GRP action by specific monoclonal antibodies results in inhibition of tumor cell growth in culture and in nude mouse xenografts. Thus, constitutively expressed GRP gene may function as a cellular oncogene under certain circumstances in small cell lung cancer. Based on these observations we are proposing to test monoclonal anti-GRP antibodies in patients.
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PMID:Chromosomal deletion, gene amplification, alternative processing, and autocrine growth factor production in the pathogenesis of human lung cancer. 333 4

These studies of lung cancer suggest that a number of molecular mechanisms may be important in the pathogenesis of lung cancer, especially SCLC. An inherited predisposition to develop SCLC may correlate with a nonfunctional, recessive allele for a gene (McKusick #18228, McKusick 1986) that maps to chromosome region 3p(14-23). Individuals at risk would be heterozygous for this allele in their germ line, carrying one copy of a normal functional gene and one mutant, recessive allele. Exposure to carcinogens, in particular cigarette smoke, can produce somatic genetic changes such as chromosomal deletion or gene mutation in the functional allele of this gene, unmasking the nonfunctional allele. Loss of this normal gene may alter the regulation of cell growth, perhaps by allowing the deregulated expression of proto-oncogenes of the myc family, or autocrine growth factors such as GRP and/or its receptor. Alternatively, loss of this gene may result in the cell returning to a less differentiated developmental state where growth regulation is less stringent. Persons with this mutant gene should be at increased risk to develop SCLC, and further RFLP analysis of the 3p region in SCLC may allow identification of specific haplotypes with increased risk of developing lung cancer. If this notion is correct, one might expect to find an increased frequency of second tumors in lung cancer patients and the presence of similar chromosomal deletions in second tumors arising in SCLC patients. In this regard, cured lung cancer patients, including those with SCLC, have a tenfold increased risk of developing a second lung cancer (Fontana 1977; Cortese et al. 1983; Johnson et al. 1986b). In fact, a chromosome 3p deletion along with other chromosomal abnormalities was identified in acute erythroleukemia cells arising in a long-term survivor of SCLC (Bradley et al. 1982), implicating this same region in the pathogenesis of both tumors. Other predictions include the correction of at least a portion of the defect by introducing a normal chromosome 3 into SCLC cells. While c-myc is expressed in many fetal and adult tissues, high-level expression of N- and L-myc is very restricted as to tissue and stage in the developing mouse, with N-myc expressed in the fetal but not adult lung, whereas the lung was the only adult tissue where L-myc expression was detected (Zimmerman et al. 1986). Could these patterns provide a clue to the differential expression of c-, N-, and L-myc found in different lung cancers (Nau et al. 1986)?(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular genetic analysis reveals chromosomal deletion, gene amplification, and autocrine growth factor production in the pathogenesis of human lung cancer. 347 65

Within the past few years, the measurement of serum and tissue markers has had an increasing influence on clinical decisions about initial treatment and follow-up. Lung cancer illustrates the types and importance of these various markers. This review presents data concerning the most studied and interesting markers in non-small cell (NSCLC) and small cell lung cancer (SCLC). CEA, TPA, SCC-Ag, CYFRA 21-1, ferritin, CA19-9, CA50, CA242, H-K-N-ras mutations and p53 mutation seem to be the most prolific in NSCLC, while NSE, BN/GRP, CK-BB, NCAM, IL-2R, IGF-I, transferrin, ANP, mAb (cluster 5), Le-y and c-N-L-myc mutation are markers in SCLC patients. Some of these serum markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure to allow change of the regimen. The study of these markers also may lead to a better understanding of the biological characteristics of lung cancer. The information derived from these biological studies represents the most promising avenue towards new treatment strategies, as well as attempts at secondary prevention.
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PMID:Clinical tumour markers in lung cancer. 753 17

The mRNAs encoding the c-kit protooncogene tyrosine kinase receptor and its ligand, hemopoietic stem cell factor, are coexpressed in the majority of small cell lung cancer cell lines, suggesting that an autocrine growth loop may exist. Functional c-kit protein levels correspond well with mRNA levels in these cells. We have observed that those cell lines which express the c-kit gene also express either the L- and N-myc genes; those cell lines which express the c-myc gene do not express the c-kit gene. We have determined, by analyzing several small lung cancer cell lines transfected with a c-myc expression vector, that heterologous expression of c-myc correlates with a marked down-regulation of c-kit expression. Regulation of c-kit expression by the myc gene family may be partly responsible for the differing biological properties of cell lines and tumors which express N- and L-myc versus those that express c-myc.
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PMID:c-myc expression correlates with suppression of c-kit protooncogene expression in small cell lung cancer cell lines. 768 33


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