Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The APC gene is responsible for familial adenomatous polyposis and is considered to be a tumor suppressor gene associated with development of sporadic colorectal tumors. Here we report the disruption of the APC gene caused by somatic insertion of a long interspersed repetitive element (LINE-1 sequence) into the last exon of the APC gene in a colon cancer. The inserted sequence was composed of a 3' portion of the LINE-1 consensus sequence and nearly 180 base pairs of polyadenylate tract. Furthermore, since an 8-base pair target site duplication was observed, retrotranscriptional insertion of an active LINE-1 sequence is suspected as the cause of this insertion event. This is the first report of the disruption of a tumor suppressor gene caused by somatic insertion of a mobile genetic element.
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PMID:Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. 131 68

We searched for germ-line mutations of the APC gene in 79 unrelated patients with familial adenomatous polyposis using a ribonuclease protection analysis coupled with polymerase chain reaction amplifications of genomic DNA. Mutations were found in 53 patients (67%); 28 of the mutations were small deletions and 2 were 1- to 2-base-pair insertions; 19 were point mutations resulting in stop codons and only 4 were missense point mutations. Thus, 92% of the mutations were predicted to result in truncations of the APC protein. More than two-thirds (68%) of the mutations were clustered in the 5' half of the last exon, and nearly two-fifths of the total mutations occurred at one of five positions. This information has significant implications for understanding the role of APC mutation in inherited forms of colorectal neoplasia and for designing effective methods for genetic counseling and presymptomatic diagnosis.
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PMID:Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. 131 10

Human blood monocytes (Mo) and monocyte-derived macrophages (M psi) possess cytotoxic effects against tumor cell lines when appropriately stimulated by various biological response modifiers, e.g., gamma interferon (gamma IFN) and muramyltripeptide (MTP). Activated Mo/M psi represent a new tool for the treatment of human malignancies, termed "adoptive cellular immunotherapy". Activated Mo/M psi express tissue factor procoagulant activity (PCA), which is a physiological trigger of blood coagulation. PCA was evaluated in vitro using a modification of the one-stage recalcification clotting time, and hemostatic changes were studied in vivo in cancer patients. Nine patients with peritoneal carcinomatosis were injected intraperitoneally with activated Mo and 11 patients with non-small cell lung carcinomas were infused intravenously with activated M psi. Hemostatic changes were followed using activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen level, antithrombin III (ATIII) and protein C (PC) activities. Fibrinolytic activity was estimated by euglobulin lysis time and assays for plasminogen and fibrin/fibrinogen degradation products (FDP). These assays were performed before and after each autologous infusion and on days 2 and 3. Activated Mo and M psi expressed potent PCA (85.5 +/- 7.5 U/ml for MTP activated Mo and 50 +/- 5.3 U/ml for gamma IFN activated M psi suspensions). In both groups of patients, APTT, PT, and TT underwent no significant variations. There was no significant consumption of ATIII or PC, and fibrinolysis was not activated during the study period. In the group injected intraperitoneally with MTP-activated Mo, fibrinogen showed a significant and progressive increase in relation to the development of an inflammatory reaction, reaching a maximum average value of 6.1 g/l at the end of the therapy with a concomitant increase in FDP levels. This increase was not observed after intravenous therapy with gamma IFN-activated M psi. No patient suffered from hemorrhagic or thrombotic events. In our experience, repeated injections of activated Mo or M psi expressing potent tissue factor PCA did not induce significant in vivo activation of the coagulation system in cancer patients.
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PMID:Hemostatic changes in human adoptive immunotherapy with activated blood monocytes or derived macrophages. 132 42

Two yeast artificial chromosomes (YACs) spanning a total distance of 1.1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5' end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.
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PMID:Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region. 132 52

Most adenocarcinomas of the colorectum arise in a visible benign precursor lesion, the adenoma, which is a monoclonal proliferation of dysplastic nonmalignant epithelial cells. The resultant adenoma-adenocarcinoma sequence represents the predominant pathogenetic pathway, in contrast to de novo carcinoma. Therefore, the adenoma is a tempting endpoint for chemoprevention trials. The adenoma-adenocarcinoma sequence occurs in diverse clinical settings. In familial adenomatous polyposis (FAP) syndrome, autosomal dominant inheritance of the mutated APC (adenomatous polyposis coli) gene on chromosome 5q21 typically results in thousands of adenomas in the colorectum and in lesser numbers in the proximal small bowel. Adenocarcinoma usually develops in only a few of these adenomas, typically in the left colon and duodenum. In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, autosomal dominant inheritance of an unidentified gene appears to result in small numbers of adenomas which progress frequently to adenocarcinoma, predominantly in the right or transverse colon. In familial aggregation of colorectal cancer without a recognizable syndrome, cancer and/or adenomas occur in pedigree members. In "sporadic" cancers and adenomas, family history is absent and the tumors are mainly in the left colon. Colorectal adenomas have variable characteristics including size, shape (polypoid vs. flat), villous architecture, and dysplasia. A variety of oncogenes and tumor suppressor genes are altered during progression. Epigenetic factors are important as evidenced by the disappearance of adenomas in FAP patients after ileorectal anastomosis or treatment with the nonsteroidal antiinflammatory drug sulindac. Several variations on the theme of the adenoma-carcinoma sequence are evident. Identification of the inherited and acquired genetic alterations as well as the interacting environmental factors will provide a rational basis for chemoprevention.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The adenoma-adenocarcinoma sequence in the large bowel: variations on a theme. 133 99

To examine whether the dosage effect of germ-line mutations in patients with familial adenomatous polyposis (FAP) is sufficient to cause colorectal adenomas, or an additional somatic mutation of the normal allele is required as well, we have investigated somatic mutations of the APC gene in multiple adenomas developed in one FAP patient. In addition to a 5-bp deletion of one allele present constitutionally in this patient, the normal APC allele had been lost in five of seven DNA samples extracted from small adenomas (< 3 mm in diameter) with mild or moderate atypia. This result indicates that the inactivation of both alleles of the APC gene is probably essential for the development of an early-stage adenoma, in agreement with the two-hit mutational model underlying the concept of tumor suppressor genes.
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PMID:Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). 133 60

We have isolated several genes on chromosome 5q21 region tightly linked to hereditary familial polyposis coli (FAP) and Gardner's syndrome (GS). Two of these genes (MCC and APC) were found to be somatically altered by point mutation, deletion or insertion in tumors of sporadic colorectal cancer patients. One (APC) of them was also found mutations in the germ line of both APC and GS patients. The identification of these genes has significant implications for understanding the pathogenesis of colorectal neoplasia and for the diagnosis and counseling of individuals with inherited predispositions to colorectal cancer.
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PMID:Mutations of the APC (adenomatous polyposis coli) gene in FAP (familial polyposis coli) patients and in sporadic colorectal tumors. 133 98

Splenic CD4+ T cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 2 to 3 wk after the inoculation with CSA1M cells produced IL-2 and macrophage-activating factor upon in vitro cultures. This lymphokine production was achieved without stimulation of these T cells with exogenous stimulating tumor Ag. However, elimination of APC from spleen cells resulted in almost complete abrogation of the capacity of CD4+ T cells to produce IL-2/macrophage-activating factor. The lymphokine production was regained when APC from CSA1M-bearing mice were added back to cultures. APC from normal or another syngeneic tumor (Meth A)-bearing mice failed to regain the lymphokine production. These observations demonstrated that the lymphokines were produced by CD4+ T cells from CSA1M-bearing hosts through their collaboration with APC binding CSA1M tumor Ag in the tumor-bearing state. The lymphokine-producing capacity of whole spleen cells from tumor-bearing mice reached the maximal level around 2 to 3 wk after tumor implantation but gradually decreased with the progress of tumor-bearing stages. Importantly, tumor-bearing stage-related changes were observed in a different fashion in the capacities of anti-CSA1M CD4+ T cells vs CSA1M tumor Ag-binding APC. The capacity of APC increased with the progress of tumor-bearing stages as demonstrated by the stimulation of CSA1M-immunized T cells with APC from different CSA1M-bearing stages. In contrast, the reactivity of anti-CSA1M T cells to APC from a given CSA1M-bearing stage decreased with the tumor-bearing stage. These results demonstrate a stage-related increase tumor Ag-binding APC function, as well as a reciprocal reduction in tumor Ag-responsive CD4+ T cell activity.
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PMID:Tumor-bearing mice exhibit a progressive increase in tumor antigen-presenting cell function and a reciprocal decrease in tumor antigen-responsive CD4+ T cell activity. 134 22

The MCC gene is a candidate as a tumor suppressor gene for colorectal neoplasms. Further, MCC is tightly linked to the familial adenomatous polyposis (FAP) locus by linkage and physical analysis. Hence, restriction fragment length polymorphisms (RFLPs) of this gene might be very useful for presymptomatic diagnosis of individuals in families segregating mutant alleles of the APC gene. Here we report the identification of five polymorphic systems in MCC gene (both cDNA and genomic), one of which is an insertion/deletion polymorphism that is detectable by a polymerase chain reaction method. These five RFLP systems should be useful for linkage studies in FAP and for examining loss of heterozygosity at this locus in colonic polyps and tumors.
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PMID:Insertion/deletion polymorphism and other restriction fragment length polymorphisms in the MCC gene. 134 24

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.
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PMID:Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. 134 43


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