Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenes and tumor suppressor genes are clustered around recombination hot spots or fragile sites in the genome, because double-strand break is the common initial step in translocation, deletion and gene amplification. FGFR2 gene on human chromosome 10q26 is amplified in diffuse-type gastric cancer, while WDR11 gene on human chromosome 10q26 is disrupted in glial tumors. Here, we investigated genomic structure around FGFR2 and WDR11 loci. The FGFR2 gene, consisting of 21 exons, was located within nucleotide position 485637-605687 of NT_030764.5 (reverse orientation), and WDR11 gene was located within nucleotide position 6515786-6574126 of NT_008902.12 (forward orientation). Because nucleotide position 1-91397 of NT_030764.5 corresponded to nucleotide position 6639437-6748623 of NT_008902.12, FGFR2 and WDR11 genes were found to be closely linked in tail-to-tail manner with an interval of ca. 570 kb. Due to the deletion of exon 21 within FGFR2 amplicons, exon 21 is substituted by exon 20 or other aberrant exons in aberrant FGFR2 transcripts previously isolated from KATO-III, OCUM-2M and HSC43 cells. Mapping of aberrant exons and deletion junctions around the WDR11-FGFR2 locus in KATO-III and OCUM-2M cells revealed that inverted-type recombination occurred through end joining of the FGFR2 locus on one allele and that on the other allele. Amplification of FGFR2 gene with such recombination around exon 21 results in exclusion of WDR11 gene from the FGFR2 amplicon. Tumor suppressor genes closely linked to oncogenes might be excluded from amplicon through a breakage-fusion-bridge process during oncogene amplification.
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PMID:FGFR2 and WDR11 are neighboring oncogene and tumor suppressor gene on human chromosome 10q26. 1268 85

FGFR2 is an oncogene amplified in diffuse-type gastric cancer, and WDR11 is a tumor suppressor gene disrupted in glial tumor. WDR11-FGFR2 locus on human chromosome 10q26 is one of cancer-related recombination hot spots. In this study, we investigated recombination and nucleotide substitution around the WDR11-FGFR2 locus during evolution by using bioinformatics. Inter-chromosomal comparison revealed that the human BAG3-FGFR2-TACC2 region was paralogous to the human BAG4-FGFR1-TACC1 region. Inter-specific comparison on the BAG3-FGFR2-TACC2 region revealed that HTPAPL-WDR11-FGFR2 locus containing species-specific insertion or deletion was one of evolutionary recombination hot spots. Between human and mouse, coding-region nucleotide substitution rate and amino-acid substitution rate were significantly lower in the HTPAPL-WDR11-FGFR2 locus than in the surrounding locus (P<0.0001). The HTPAPL-WDR11-FGFR2 locus was more susceptible to recombination than to nucleotide substitution. Detailed comparison of human and mouse genomes could identify evolutionary recombination hot spots overlooked during gross comparison of human and mouse genomes. Because DNA double-strand break is the initial step in various types of recombination including chromosomal translocation, rearrangement, deletion, gene amplification, retroviral integration and retrotransposition, it is reasonable that the HTPAPL-WDR11-FGFR2 locus is the recombination hot spot during evolution as well as during carcinogenesis. Therefore, comparative genomics might be applicable to identification of recombination hot spots and genes related to cancer.
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PMID:Recombination cluster around FGFR2-WDR11-HTPAPL locus on human chromosome 10q26. 1268 93

MYC, ERBB2, MET, FGFR2, CCNE1, MYCN, WNT2, CD44, MDM2, NCOA3, IQGAP1 and STK6 loci are amplified in human gastric cancer. It has been reported that the gene corresponding to EST H16094 is co-amplified with ERBB2 gene in human gastric cancer. Here, we identified and characterized the gene corresponding to EST H16094 by using bioinformatics. BLAST programs revealed that EST H16094 was derived from the uncharacterized MGC9753 gene. Two ORFs were predicted within human MGC9753 mRNA, and ORF1 (nucleotide position 18-980 of NM_033419.1) was predicted as the coding region of human MGC9753 mRNA based on comparative genomics. Nucleotide sequence of mouse Mgc9753 mRNA was next determined in silico by modification of AK052486 cDNA (deleting C at the nucleotide position 37). Human MGC9753 and mouse Mgc9753 proteins were 320-amino-acid seven-transmembrane receptors with the N-terminal six-cysteine domain and an N-glycosylation site (85.0% total-amino-acid identity). Human MGC9753 protein showed 90.6% total-amino-acid identity with human CAB2 aberrant protein, which lacked the third-transmembrane domain of MGC9753 due to frame shifts within ORF. Human MGC9753 gene, consisting of eight exons, were clustered with PPP1R1B, STARD3, TCAP, PNMT, ERBB2, MGC14832 and GRB7 genes within the 120-kb region. PPP1R1B, STARD3, MGC9753, ERBB2 and GRB7 genes are co-amplified in several cases of gastric cancer. This is the first report on comprehensive characterization of the amplicon around the PPP1R1B-STARD3-TCAP-PNMT-MGC9753-ERBB2-MGC14832-GRB7 locus on human chromosome 17q12.
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PMID:MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. 1273 7

The epidermal growth factor (EGF) receptor and its various ligands (EGF, TGF-alpha, amphiregulin, heparin-binding (HB)-EGF, heregulin, betacellulin) seem to be involved in the growth regulation of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. However, few quantitative data investigating the impact of tumor-EGF receptor levels in gastrointestinal carcinomas on tumor stage and prognosis are available. Therefore, EGF receptors were quantitatively determined in colorectal carcinomas in comparison to adjacent normal mucosa by 125I[EGF]-binding studies. EGFR capacity was increased in advanced invasive colorectal carcinomas (T1/2 vs. T3/4 tumors, p<0.001) and advanced UICC stages (UICC I vs. UICC II/III, p<0.001). These findings were confirmed with quantitative 125[I]EGF autoradiography performed on frozen tissue slides and analyzed by laser densitometry (p=0.020). EGF receptor analysis with immunohistochemistry with EGFR antibodies directed against the extracellular domain of the receptor was not correlated with tumor invasion or prognosis. mRNA-expression of EGFR ligands was investigated using semiquantitative RT-PCR amplification using specific primers. RT-PCR transcripts of EGFR ligands (EGF, TGF-alpha, HB-EGF, and amphiregulin) were detected in both carcinomas and normal mucosa, indicating that autocrine growth stimulation of colorectal carcinomas is mediated by coexpression of EGF receptor ligands and upregulation of EGF receptors. Survival of colorectal cancer patients with increased tumor EGF receptor levels was significantly reduced in comparison to patients with low/unchanged tumor EGF receptor levels (mean survival+/-SD, 36.2+/-4.0 vs. 46.8+/-4.3 months; p=0.017). Further studies investigating EGF receptor levels in gastric cancer patients have shown that increased tumor EGF receptor levels were associated with poor prognosis in gastric cancer patients with tumors localized distal from the cardia. Several specific EGF receptor tyrosine kinase inhibitors have recently entered clinical phase I-III studies, with promising antitumor effects in several tumors, including gastrointestinal cancer. Therefore, patients with invasive gastric or colorectal carcinomas might benefit from therapies specifically blocking EGFR-mediated signal transduction.
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PMID:Clinical implications of the EGF receptor/ligand system for tumor progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options. 1279 Mar 26

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.
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PMID:Molecular dimensions of gastrointestinal tumors: some thoughts for digestion. 1451 68

Cancer vaccine therapy is one of the new treatment modalities for gastric cancer at the advanced stage. In this study, we have identified HER2 peptide epitopes restricted by HLA-A24, which is one of the most common alleles in Japanese. We generated immature DCs from PBMCs in a HLA-A24+, HER2+ gastric cancer patient. Immature DCs were co-incubated with irradiated PC-9 cell line, and then autologous PBMCs were co-incubated with PC-9-derived antigen-loaded DCs. As a result, we were able to generate HER2 reactive, HLA-A24-restricted CTL lines. The CTL's specificity was evaluated with ELISPOT analysis and cytotoxic assay. The CTLs specifically recognized cancer cells expressing HLA-A24 and HER2. We synthesized a set of HLA-A24 binding, HER2-derived peptides to identify HLA-A24 restricted peptide epitopes derived from HER2. In conclusion, we were able to identified HER2 peptide epitopes restricted by HLA-A24, suggesting that these epitopes will be new targets for cancer vaccine therapy.
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PMID:[Generation of HER2 specific, HLA-A24 restricted CTLs derived from gastric cancer patients]. 1461 24

In order to investigate the roles of ERK1/2 mitogen-activated protein kinase in vitamin E succinate (VES)-induced apoptosis in human gastric cancer SGC-7901 cells, apoptosis was observed by DAPI staining and the phosphorylation of ERK1/2 by VES at different doses and different time points was measured by western blot. The results showed that VES obviously induced cells to undergo apoptosis and apoptotic rate after 24 h and 48 h of treatment with VES at 20 micrograms/ml. VES was 14.2% and 89.4%, respectively. The expression of p-ERK was evidently reduced by VES at 5, 10 and 20 micrograms/ml for 24 h. ERK1/2 was immediately activated by VES at 20 micrograms/ml, but the expression was decreased for 2 h, then increased again and reached the top level for 12 h. The data implicated that ERK1/2 pathway might be involved in VES-induced apoptosis, but in the proliferation eventually.
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PMID:[Roles of ERK1/2 MAPK in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells]. 1496 7

On the basis of data of the Human Genome Project, it was embraced the newest information about the gene content of the human genome, the disease genes, the parasitic DNA, the single nucleotide polymorphisms, the repeat sequences, the cytoskeletons, the regulation of cell proliferation, and their medical consequences. The applicability of the acquaintance with the human genome in pathology is presented with a few examples of our own. The significance of the single nucleotide polymorphisms in susceptibility to, or protection from, a host of disease is illustrated by the example of the allele variation of Apo-E gene. The copy number of the N-myc gene in neuroblastomas and HER2/neu gene in breast carcinomas was determined with quantitative PCR techniques. The monoclonally increased abnormal p53 protein expression was found in small cell lung cancer (in 90% frequency), in oro-pharyngeal carcinomas (82%), in esophageal squamous cell carcinomas (59%) in stomach cancer (33%), in colon carcinomas (27%) and in soft tissue sarcomas (13%). These data advert to the fact that the mutation of the p53 gene is much more frequent in those tumors in which the basic tissue is directly exposed to with the environmental carcinogens. It is now known, that near the repetitive sequences, gene rearrangement can more easily be evolve. Finally, we have determined the conditions of the accomplishment of the molecular pathological diagnosis: (1) It is applicable, when the classic morphology does not eventuate a conclusive result. (2) Well known and validated gene alterations are admissible to diagnostic purpose. (3) Only standard methods are applicable along with positive and negative controls. (4) The result has to correlate with the morphological picture, the immunohistochemical profile and the clinical data. (5) It is necessary to be able to appropriately interpret the molecular biological result, which is then incorporated in the pathological report. (6) The ethical, legal and social consequences must be considered.
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PMID:[Effect of learning about the human genome on the development of pathology]. 1497 56

DNA copy number amplification at the chromosomal region of 17q is frequent in gastric cancer. Recently 17q21 was identified as the critical region for the amplicon formation because this region harbors the ERBB2 oncogene and several other targets, such as TOP2A and DARPP32. In our study, we characterized the amplification (52 cases) and expression (29 cases) levels of ERBB2, TOP2A and DARPP32 in gastric cancer samples. These 3 genes were concomitantly amplified in 17% of the intestinal type of gastric adenocarcinoma. However, the expression levels were independent, showing overexpression of DARPP32 (48%), TOP2A (17%) and ERBB2 (3%) studied by quantitative real-time PCR. The most frequently overexpressed gene, DARPP32, exhibited strong protein overexpression in 45% (30/66) of the cases in immunohistochemical study of gastric cancer tumor tissue array. Additional studies are required to thoroughly understand the biological significance of these genes in gastric cancer.
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PMID:Coamplified and overexpressed genes at ERBB2 locus in gastric cancer. 1499 76

PPP1R1B-STARD3-TCAP-PNMT-PERLD1-ERBB2-MGC14832-GRB7 locus at human chromosome 17q12 is frequently amplified in human gastric cancer and breast cancer. Here, we compared human GSDML-GSDM locus with rodent genomes by using bioinformatics. Rodent ortholog of human GSDML was not identified. Rat Gsdm gene was identified within rat genome clone CH230-28N16 (AC119462.4), and was mapped to rat chromosome 10q31. Rat Gsdm gene, consisting of 12 exons, encoded a 446-amino-acid protein, which showed 86.3% and 32.3% total-amino-acid identities with human GSDM and GSDML, respectively. Mouse Gsdm-like 1 (Gsdml1) and Gsdml2 genes were identified within mouse genome clone RP23-438D7 (AL591125.20). Gsdml1 and Gsdml2 genes were found to encode 456- and 443-amino-acid proteins, respectively. Mouse 2200001G21Rik cDNA (AK008613.1) was a partial cDNA derived from mouse Gsdml2 gene. Mouse Gsdml1 and Gsdml2 were also more homologous to human GSDM than to human GSDML. Mouse Gsdml1, Gsdml2 and Gsdm genes, existing in the tandem homologous gene cluster, was mapped to mouse chromosome 11D. Mouse Gsdml1-Gsdml2-Gsdm gene cluster was predicted to be generated due to triplication of mouse Gsdm gene, while GSDML gene was predicted to be generated due to duplication of GSDM gene. Evolutionary recombination hotspot around the GSDML-GSDM locus was closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon. The evolutionary recombination hotspot and oncogenomic recombination hotspot might be clustered around the fragile sites within the human genome.
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PMID:Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon. 1501 Aug 12


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