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)

Three human T-cell clones with activated killer activity (5B5, 5C1, and 7B5) which could lyse various tumor cell lines were established. The cytotoxic activity of these clones was decreased by incubation with anti-CD3 monoclonal antibody, suggesting that they recognized tumor cells by T-cell antigen receptor. A monoclonal antibody which blocked the cytotoxic activity of clone 5B5 was obtained. This antibody (N1977) blocked the binding and cytotoxic activity of clone 5B5 at the target cell level, suggesting that the antigen defined by N1977 antibody, designated as ATM-1, was a target molecule recognized by 5B5 cells. ATM-1 in the conditioned medium of a cancer cell line (NBT-2) and serum from a patient with lung cancer was characterized by following its immunoreactivity. On gel filtration, both the conditioned medium and the serum gave three peaks of ATM-1 immunoreactivity, corresponding to approximate molecular weights of 1,200,000, 700,000, and 120,000, respectively. They were chromatofocused at pH 4.0, 4.8, and 6.5, respectively. The high molecular weight forms were shown to be molecules with the disulfide-linked elementary glycoprotein with ATM-1 immunoreactivity and approximate molecular weight of 120,000. Most of the molecules with ATM-1 immunoreactivity bound to both concanavalin A and wheat germ agglutinin, and their binding activity to the antibodies was lost by treatment at 60 degrees C for 30 min. An assay of ATM-1 level in sera was performed by a sandwich enzyme immunoassay. The following positive percentages were obtained from preliminary clinical studies: breast cancer, 67% (8 of 12 cases); hepatocellular carcinoma, 83% (10 of 12 cases); gastric cancer, 58% (7 of 12 cases); lung cancer, 41% (5 of 12 cases); hematological malignancies, 0% (0 of 9 cases); systemic lupus erythematosus, 0% (0 of 8 cases); rheumatoid arthritis, 0% (0 of 8 cases).
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PMID:Identification of a tumor-associated target antigen, ATM-1, for a human T-cell clone with activated killer activity and its existence in sera of cancer patients. 304 79

This paper referred to primary immunodeficiency diseases (PID)-malignancy association in autopsy cases in Japan. The occurrence of malignant neoplasms almost centered upon ataxia-telangiectasia among PID in Japan. It seems to be due to extremely shorter life span in Japanese patients with PID except for in those with ataxia-telangiectasia, compared with that in European and American patients. Most of the malignant neoplasms seen in Japanese patients with PID were epithelial and were seen mostly in older patients, while lymphoreticular tumors were rare. Gastric cancer was the most frequent of the epithelial tumors.
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PMID:Immunodeficiency-malignancy association at autopsy in Japan. 665 Jan 70

Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disease characterised by cutaneous telangiectasia, cerebellar ataxia, immunodeficiency, high sensitivity to ionising radiation, chromosomal instability and an increased risk of cancer. The gene mutated in A-T patients, ATM, is located on chromosome 11q22-23. ATM heterozygotes are thought to have a high tendency to develop malignancies, such as breast cancer. In order to determine the contribution of heterozygous ATM mutation to cancer, studies of cancer-affected patients have been undertaken in non site-specific cancer families and sporadic breast cancer cases. No evidence of an important role of ATM heterozygous mutations has been shown. In order to give another contribution to these results, we tried to define a specific family phenotype according to the most common cancers observed in ATM heterozygotes. Breast and gastric cancers appear to be the most frequent malignancies in A-T carriers and one ATM germ-line mutation has been described in a breast/gastric cancer family. Therefore we further investigated the role of ATM mutation in additional breast/gastric cancer families. In eighteen families associating these two malignancies, we used the protein transcription/translation test to detect ATM mutations in the index case from each family. We found one case of ATM mutation which did not cosegregate with the gastric cancer in the family.
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PMID:No evidence for constitutional ATM mutation in breast/gastric cancer families. 959 4

Maintenance of genomic stability depends on the appropriate cellular responses to DNA damage and the integrity of the DNA repair systems. We analyzed stomach tumors with microsatellite instability (MSI) for frameshift mutations in several potential targets of the mutator phenotype involved in DNA damage-response pathways, such as the ataxia telangiectasia mutated protein-related protein (ATR)-CHK1-Cdc25c pathway, and DNA repair. High frequency of mutations was found within ATR [5 (21%) of 23], MED1 [10 (43%) of 23], hMSH3 [13 (56%) of 23], and hMSH6 [10 (43%) of 23] genes. Also, a low frequency of mutations within the CHK1 gene was detected in 9% (2 of 23) of tumors. No mutations of hMLH3, ATM, BRCA1, or NBS1 genes were detected. These results confirm ATR, MED1, and CHK1 as targets of the mutator pathway in stomach tumorigenesis, and also suggest a potential role of MED1 increasing, together with hMSH3 and hMSH6, the genomic instability in the mutator pathway as a secondary mutator. Furthermore, these results suggest that the inhibition of the ATR-CHK1 DNA damage-response pathway might be involved in the tumorigenesis of gastric cancer with microsatellite instability.
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PMID:Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. 1169 84

Ataxia telangiectasia mutated (ATM) is the gene mutated in the genetic disorder ataxia telangiectasia (AT), the symptoms of which include sensitivity to radiation and an increased risk of cancer. ATM is a kinase involved in activating the appropriate damage-response pathway, leading to either cell-cycle arrest or apoptosis, and is therefore a key checkpoint molecule in regulating cell-cycle response to DNA damage and responsible for maintenance of genome integrity. However, little is known about the association of ATM mutations with human gastric cancer (HGC). In order to determine the mutation and mRNA expression changes of the ATM gene in HGC, we performed analyses by denaturing high-performance liquid chromatography (DHPLC), DNA sequencing and RT-PCR technique on 13 human gastric tumor cell lines and 30 cases of fresh tumor specimens matched normal tissue. We compared the potential effect of the ATM gene mutation and cell behavior including cell-cycle arrest and induction of apoptosis in the tumor cell lines MGC803 and BGC823 with and without ionizing radiation (IR) exposure. Our data show that frequent variations were observed at 10 exons and 2 cDNA fragments which covered 8 other exons of the ATM gene as 5 out of 13 on the cell lines (38.5%) and 2 out of 30 cases in the tissue specimens (6.7%). All point mutations were confirmed as base substitutions (5982T-C; 6620A-G; 8684G-G/A; 9389C-G) and deletions (1079delC) by use of DNA sequencing. Among the mutations, one was reported previously in breast cancer, the other five have not yet been reported. The expression of ATM was significantly lower in five cell lines (MGC803; MKN45; SGC7901; GES and SUN-1) than in two others (BGC823 and RF48). G2/M cell-cycle arrest and apoptosis were observed in ATM-deficient MGC803 cells challenged with IR. A transient up-regulation of p53 occurred 1h post-IR in BGC823 cells but not in MGC803 cells. Our findings suggest that ATM mutations might be a pathogenic factor for an increased risk of gastric cancer, and the dysfunction of ATM may lead to a hypersensitivity to ionizing radiation in gastric cancer cells, possibly by a p53-dependent pathway.
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PMID:Alteration of the ATM gene occurs in gastric cancer cell lines and primary tumors associated with cellular response to DNA damage. 1470 17

Camptothecin (CPT) is a potent inhibitor of DNA topoisomerase I with a wide spectrum of anti-tumor activity. Relatively little information is available regarding the relation of known topoisomerase-mediated DNA damage with other intracellular pathways. To gain an insight into the intracellular molecular mechanisms of Topoisomerase I inhibitor camptothecin-mediated DNA damage leading to cell death, we used a high-density cDNA microarray to assess sensitive early gene expression profiles in SGC7901 (gastric cancer), Hela (cervical adenocarcinoma), K562 (chronic myelogenous leukemia) and HL60 (promyelocytic leukemia) tumor cells stimulated with camptothecin for 1 h at the concentrations of GI50 (50 % growth inhibition after 24 h of treatment). Analysis of the differentially expressed genes obtained 29 response genes common to all four cell lines. Moreover, these cell lines also shared the direction of regulation. Most of these common response genes were functionally related to cell proliferation or apoptosis, and some of them were involved in ATM (ataxia-telangiectasia mutated) and ATR (ATM-and Rad3 related) checkpoint pathways, JNK (c-Jun N-terminal kinase) pathway, the survival phosphatidylinositol (PI) 3 kinase-Akt-dependent pathway, mitochondrial cell death pathway, endoplasmic reticulum (ER)-related cell death pathway, and to ubiquitin/proteasome dependent protein degradation pathway. The data provides evidence for a linkage between topoisomerase-mediated DNA damage and intracellular signaling events, which may facilitate our understanding of the camptothecin mediated molecular mechanisms of action.
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PMID:Analysis of common gene expression patterns in four human tumor cell lines exposed to camptothecin using cDNA microarray: identification of topoisomerase-mediated DNA damage response pathways. 1636 68

The role of telomere in drug resistance has not been clearly understood. Recent studies have been focused on telomerase activity and telomere length, but the findings are still controversial. It's been found that DNA double-strand breaks induced by anticancer drugs or irradiation increase TRF2 expression as an early response to DNA damage, which inhibits activation of ATM-dependent DNA damage response network, indicating TRF2 might probably be a general DNA-repair factor rather than merely a telomere-binding factor. In this study, the possible involvement of telomerase, telomere and TRF2 in DNA damage response and drug resistance was investigated. Telomere length was found elongated in multidrug-resistant variants of gastric cancer cell line SGC7901 treated with adriamycin or etoposide, however, drug-treatment per se had no effect on telomere length. Telomerase activity and TRF2 expression were upregulated after treatment, but not TRF1. TRF2 upregulation was more dramatic in drug-resistant cells and occurred before the expression of ATM, gammaH2AX and p53. Moreover, TRF2 inhibited the expression of ATM-dependent DSB responsive genes. Inhibition of TRF2 expression by RNA interference in drug-resistant cells partially reversed its resistance phenotype and overexpression of TRF2 in SGC7901 promoted its resistance phenotype. Taken together, current results indicate that TRF2 plays an important role in DNA damage response, and is involved in drug resistance of gastric cancer. Further study of the biological functions of TRF2 might be helpful to dissect the molecular mechanism of multiple drug-resistance and generate novel target to overcome it.
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PMID:TRF2 promotes multidrug resistance in gastric cancer cells. 1696 91

We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis.
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PMID:Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis. 1737 10

Several genes are associated with hereditary susceptibility to breast cancer. Most notably these include BRCA1 and BRCA2; however, other less common gene mutations which confer elevated breast cancer risk are associated with Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, ataxia-telangiectasia heterozygosity and hereditary diffuse gastric cancer. In this article we highlight the genetic epidemiology, gene function, genotype-phenotype correlations, cancer risks and clinicopathologic findings for the cancer susceptibility genes related to these syndromes. We also examine genes, such as CHEK2, which confer a lower penetrance for breast cancer in comparison to these highly penetrant genes.
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PMID:Susceptibility to breast cancer: hereditary syndromes and low penetrance genes. 1791 39

DNA damage response (DDR) pathways maintain genomic stability. A 657del5 mutation of NBS1, a key DDR component, causing the rare cancer-predisposing Nijmegen breakage syndrome has been reported nearly exclusively in Slavic populations. In this study, we describe the first identification in a Japanese population of an unprecedented type of heterozygous NBS1 mutant, termed IVS11+2insT, lacking the MRE11- and ATM-binding site at the COOH terminus. Profoundly defective in crucial binding to MRE11, MDC1, BRCA1, and wild-type NBS1, the mutant caused impaired ATM phosphorylation in response to low-dose irradiation in a heterozygous state. Importantly, whereas IVS11+2insT was found in only 2 (0.09%) of 2,348 control subjects, it was identified in 2% (2 of 96) of heterozygotes with gastric cancer, 0.8% (3 of 376) of those with colorectal cancer, and 0.4% (2 of 532) of those with lung cancer, which were comparable to frequencies reported for other DDR-related genes known to confer cancer susceptibility. The presence of the heterozygous IVS11+2insT mutation seemed to be associated with an increased risk for gastrointestinal cancers, with an odds ratio of 12.6 and 95% confidence interval (95% CI) of 2.05 to 132.1 (P = 0.0001). The odds ratios separately calculated for gastric and colorectal cancers were 25.0 (95% CI, 1.78-346.0) and 9.43 (95% CI, 1.08-113.1), respectively. These findings suggest that IVS11+2insT is associated with an increased risk for the development of certain types of common cancers, warranting future investigation including detailed phenotypic characterization of age of onset and penetrance in heterozygotes, as well as screening in other ethnic groups.
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PMID:Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer. 1805 40


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