Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is the leading cause of death in both women and men in the United States and many European countries. Molecular cytogenetic and LOH analyses of non-small cell lung cancer have shown somatic genetic alterations in a variety of chromosomes, such as 1p, 3p, 5q, 8p, 9p, 11p, 11q and 17p. Allelic deletions of the known tumor suppressor gene APC at 5q21 are frequently observed in advanced stages of lung cancer and have been correlated with poor prognosis in previous reports. We investigated 33 cases of NSCL for LOH at 5q21: 22 squamous cell and 11 adenocarcinomas. Normal and tumor cells were microdissected from paraffin embedded tissues and PCR amplification was performed utilising the specific markers D5S299 and D5S346 at 5q21 and PYGM at 11q13, respectively. Clinicopathological data, survival and recurrence rates were obtained in all cases. We detected LOH at 5q21 in 4/9 (44%) informative adenocarcinomas and in 13/16 (81%) informative SCC. LOH was frequent in early stages (12/15 stage I cases) and did not correlate with recurrence or poor survival. Our results show that LOH at 5q21 is more frequent in squamous cell carcinomas than in adenocarcinomas, is frequent in early stages of the disease, and does not have prognostic significance.
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PMID:LOH at the APC/MCC gene (5Q21) is frequent in early stages of non-small cell lung cancer. 1054 31

In this study, we show that Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, suppresses host immune reactivity against lung cancer. In two different weakly immunogenic murine lung cancer models, intermittent administration of THC (5 mg/kg, four times/wk i.p. for 4 wk) led to accelerated growth of tumor implants compared with treatment with diluent alone. In contrast to our findings in immunocompetent mice, THC did not affect tumor growth in tumor-bearing SCID mice. The immune inhibitory cytokines, IL-10 and TGF-beta, were augmented, while IFN-gamma was down-regulated at both the tumor site and in the spleens of THC-treated mice. Administration of either anti-IL-10- or anti-TGF-beta-neutralizing Abs prevented the THC-induced enhancement in tumor growth. Both APC and T cells from THC-treated mice showed limited capacities to generate alloreactivity. Furthermore, lymphocytes from THC-treated mice transferred the effect to normal mice, resulting in accelerated tumor growth similar to that seen in the THC-treated mice. THC decreased tumor immunogenicity, as indicated by the limited capacity for tumor-immunized, THC-treated mice to withstand tumor rechallenge. In vivo administration of a specific antagonist of the CB2 cannabinoid receptor also blocked the effects of THC. Our findings suggest the THC promotes tumor growth by inhibiting antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway.
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PMID:Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. 1086 Oct 74

Constitutive activation of the Wnt signaling pathway as a result of genetic alterations of APC, AXIN1, and CTNNB1 has been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. To investigate the pathogenetic significance of constitutive activation of the Wnt signaling pathway in human lung carcinogenesis, CTNNB1 alterations in exon 3, a region known to represent a mutation hot spot, were screened in 46 lung cancer cell lines and 47 primary lung cancers. Missense mutations causing substitutions of Ser/Thr residues critical for regulation by GSK-3beta were detected in one (2%) of the cell lines, A427, and two (4%) of the surgical specimens. The three lung cancers with CTNNB1 mutations were adenocarcinomas. To explore the prevalence of constitutive activation of the Wnt signaling pathway in human lung cancer, we assessed 15 lung cancer cell lines representing major histological subtypes of lung cancers for constitutive Tcf transcriptional activity (CTTA). CTTA was observed only in the A427 adenocarcinoma cell line, but not in the remaining 14 cell lines. The data indicate that constitutive activation of the Wnt signaling pathway caused by CTNNB1 mutation is involved in the development and/or progression of a subset of lung carcinoma, preferentially in adenocarcinoma.
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PMID:Constitutive activation of the Wnt signaling pathway by CTNNB1 (beta-catenin) mutations in a subset of human lung adenocarcinoma. 1117 Feb 92

Human chromosome 11p15.3 is associated with chromosome aberrations in the Beckwith Wiedemann Syndrome and implicated in the pathogenesis of different tumor types including lung cancer and leukemias. To date, only single tumor-relevant genes with linkage to this region (e.g. LMO1) have been found suggesting that this region may harbor additional potential disease associated genes. Although this genomic area has been studied for years, the exact order of genes/chromosome markers between D11S572 and the WEE1 gene locus remained unclear. Using the FISH technique and PAC clones of the flanking markers we determined the order of the genomic markers. Based on these clones we established a PAC contig of the respective region. To analyse the chromosome area in detail the synteny of the orthologous region on distal mouse chromosome 7 was determined and a corresponding mouse clone contig established, proving the conserved order of the genes and markers in both species: "cen-WEE1-D11S2043-ZNF143-RANBP7-CEGF1- ST5-D11S932-LMO1-D11S572-TUB-tel", with inverted order of the murine genes with respect to the telomere/centromere orientation. The region covered by these contigs comprises roughly 1.6 MB in human as well as in mouse. The genomic sequence of the two subregions (around WEE1 and LMO1) in both species was determined using a shotgun sequencing strategy. Comparative sequence analysis techniques demonstrate that the content of repetitive elements seems to decline from centromere to telomere (52.6% to 34.5%) in human and in the corresponding murine region from telomere to centromere (41.87% to 27.82%). Genomic organisation of the regions around WEE1 and LMO1 was conserved, although the length of gene regions varied between the species in an unpredictable ratio. CpG islands were found conserved in putative promoter regions of the known genes but also in regions which so far have not been described as harboring expressed sequences.
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PMID:Comparative architectural aspects of regions of conserved synteny on human chromosome 11p15.3 and mouse chromosome 7 (including genes WEE1 and LMO1). 1152 26

The wealth of data in basic science and translational research may often represent a conundrum for clinical oncologists, who need to selectively consider this abundant information and translate it into therapeutic decisions. For the sake of simplicity, we have classified the multiplicity of genetic abnormalities in five repertoires that are rapidly assessable and useful for stratification in clinical trials: allelic imbalance, aberrant promoter methylation, gene mRNA overexpression, microtubule alterations, and polymorphisms. Allelic imbalance refers to chromosomal instability, which is a major feature of cancer, and innovative techniques used in colorectal cancer should also be implemented in lung cancer. Epigenetic changes (variations in transcription levels) have been extensively studied in non-small cell lung cancer. Methylation techniques have shown that these epigenetic changes commonly occur at the same frequency in numerous genes, both well-known ( FHIT, APC, p16 ) and recently discovered ( TMS1, RASSF1 ) in non-small cell lung cancer and in breast cancer. Innovative techniques like quantitative polymerase chain reaction can determine gene expression profiles, mainly overexpression of mRNAs, which may be related to resistance to specific cytotoxic drugs. In the near future, we hope these profiles can be used to individualize chemotherapy. Multiple microtubule alterations related to overexpression of different genes can also be used to predict response to taxanes and Vinca alkaloids. Finally, the assessment of polymorphisms could enable us to understand their functional consequences in chemotherapy response.
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PMID:Translational oncogenomics: toward rational therapeutic decision-making. 1188 Jul 7

Recent analyses of global and gene-specific methylation patterns in cancer cells have suggested that cancers from different organs demonstrate distinct patterns of CpG island hypermethylation. Although certain CpG islands are frequently methylated in many different kinds of cancer, others are methylated only in specific tumor types. Because distinct patterns of CpG island hypermethylation can be seen in tumors from different organs, it seems likely that histological subtypes of cancer within a given organ may exhibit distinct methylation patterns as well. The goal of our study was to determine whether the patterns of CpG island hypermethylation could be used to distinguish between different histological subtypes of lung cancer. We analyzed the methylation status of 23 loci in 91 lung cancer cell lines using the quantitative real-time PCR method MethyLight. Genes PTGS2 (COX2), CALCA, MTHFR, ESR1, MGMT, MYOD1, and APC showed statistically significant differences in the level of CpG island methylation between small cell lung cancer (SCLC) and non-small cell lung cancer cell lines (NSCLC). Hierarchical clustering using a panel consisting of these seven loci yielded two major groups, one of which contained 78% of the SCLC lines. Within this group, a large cluster consisted almost exclusively of SCLC cell lines. Our results show that DNA methylation patterns differ between NSCLC and SCLC cell lines and suggest that these patterns could be developed into a powerful molecular marker to achieve accurate diagnosis of lung cancer.
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PMID:Hierarchical clustering of lung cancer cell lines using DNA methylation markers. 1189 80

Loss of heterozygosity at the polymorphic loci on the long arm of chromosome 5 is observed in about 80% of human small-cell lung cancer (SCLC). Absence of inactivating mutations in the APC gene on 5q14 suggests the involvement of another tumor suppressor gene. We found a homozygous deletion of sequence tagged site sequence G73332on 5q12.3 in 2 of 12 human SCLC cell lines, Lu130 and Lu134. One copy of chromosome 5q was lost in these cell lines, and the remaining allele had a deletion in a more restricted region. A polymerase chain reaction-based analysis of yeast artificial chromosome, bacterial artificial chromosome (BAC), and lambda-phage clones narrowed the region of homozygous deletion to a fragment cloned within one BAC. Sequencing analysis revealed that a DNA fragment of approximately 25 kb was deleted interstitially, probably because of recombination through Alu repetitive sequences in Lu130 and Lu134 cells. This deletion was not detected in normal lymphocyte DNA from 98 unrelated individuals. No candidate genes, however, were detected within this region or in the adjacent 150-kb fragment. The absence of microsatellite instability and the presence of an interstitial deletion as well as gross chromosomal aberration suggest that the genomic integrity of Lu130 and Lu134 cells might possibly be affected by Alu-mediated recombination in addition to chromosomal instability. The identical breakpoints in Lu134 and Lu135 cells as well as the same genotypes at all 33 polymorphic loci examined on various chromosomes strongly suggest that these cell lines share the same genetic materials, at least in part, during the establishment or propagation of cell lines.
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PMID:Homozygous deletion on the chromosomal region 5q12.3 in human lines of small-cell lung cancers. 1211 68

In the present study, we used 22 microsatellite markers flanking to or within 13 known or candidate tumor suppressor genes (TSGs) to detect loss of heterozygosity (LOH) in these chromosomal regions among 41 cases of non-small cell lung cancer, including 28 squamous cell carcinoma (SCC) and 13 adenocarcinoma (ADC). The studied TSGs comprised FHIT, VHL, APC, PRLTS, p16, IFNA, PTEN, p57, ATM, p53, BRCA1, DPC4 and DCC. Our data demonstrated frequent allelic losses of FHIT, p53, IFNA, VHL and p16 in both SCC and ADC. PTEN and ATM showed the least frequency of LOH, while no deletion of BRCA1 was detected in all tumor samples. LOH analysis of PRLTS was extended to 26 cases of ADC, which demonstrated significantly higher frequency of LOH than SCC. Our data indicated a possible correlation between specific TSG(s) and either histological type of lung cancer, and more attention should be paid to the PRLTS gene, which might play an important role in the development of ADC.
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PMID:Deletion of tumor suppressor genes in Chinese non-small cell lung cancer. 1212 91

Recently, we reported that a recurrent translocation, t(1;3)(p36;p21) is closely associated with prior chemotherapy including alkylating agents, assessing eight patients with various hematologic malignancies (Genes, Chromosomes and Cancer 34:186-192), 2002). Furthermore, we delineated the 1p36 breakpoint in two patients lying between RP11-BAC47P3 and RP5-PAC963K15 at 1p36.3 with a small deletion near the breakpoint. In one of them, we also found deletion at 3p21.3 with cosNRL9 probe, which is included in a 370-kb lung cancer homologous deletion region. However, due to scantiness of the patient materials at that time, we could not determine the precise breakpoint at 1p36 or 3p21 in any of the patients. In this report, we identified the 1p36 and 3p21 breakpoints of an AML (M3) patient who is included in the previous patient series. The patient showed t(1;3)(p36;p21) together with t(15;17) at the third relapse. With FISH using BAC/PAC probes, we determined the 1p36 breakpoint within RP11-295B1 at 1p36.2 and the 3p21 breakpoint between RP11-3B7 and RP11-901L6 at 3p21.3. There was no deletion around the two breakpoints in this patient. To the best of our knowledge, this is the first report that has identified the precise breakpoint of t(1;3)(p36;p21) translocation. It is obvious that the 1p36.2 and 3p21.3 breakpoints of this patient are different from those of the previous patients, suggesting that the genes and the molecular event is different from those of the previous patients. The patients with t(1;3)(p36;p21) should be subclassified according to the precise breakpoints or the genes involved.
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PMID:Identification of the breakpoints at 1p36.2 and 3p21.3 in an AML(M3) patient who had t(1;3)(p36.2;p21.3) at the third relapse. 1237 31

The effects of pituitary adenylate cyclase activating polypeptide (PACAP) on human lung cancer cell line NCI-1299 mitogen activated protein kinase (MAPK) tyrosine phosphorylation and vascular endothelial cell growth factor (VEGF) expression were investigated. PACAP-27 (100 nM) increased MAPK tyrosine phosphorylation 3-fold, 5 min after addition to NCI-H1299 cells. PACAP caused tyrosine phosphorylation in a concentration-dependent manner being half-maximal at 10 nM PACAP-27. PACAP-27 or PACAP-38 (100 nM) but not PACAP28-38 or VIP caused increased MAPK tyrosine phosphorylation using NCI-H1299 cells. Also, the increase in MAPK tyrosine phosphorylation caused by PACAP-27 was totally inhibited by 10 microM PACAP(6-38), a PAC(1) receptor antagonist or 10 microM PD98059, a MAPKK inhibitor. These results suggest that PAC(1) receptors regulate tyrosine phosphorylation of MAPK in a MAPKK-dependent manner. PACAP-27 (100 nM) caused increased VEGF mRNA in NCI-H1299 cells after 8 h. The increase in VEGF mRNA caused by PACAP-27 was partially inhibited by PACAP(6-38), PD98059 and H-89. Addition of VIP to NCI-H1299 cells caused increased VEGF mRNA, which was totally inhibited by H89, a PKA inhibitor. These results suggest that PAC(1) and VPAC(1) receptors regulate VEGF expression in lung cancer cells.
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PMID:PACAP-27 tyrosine phosphorylates mitogen activated protein kinase and increases VEGF mRNAs in human lung cancer cells. 1240 25


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