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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrations of the APC gene, which plays an important role in the genesis of familial adenomatous polyposis and colorectal carcinoma, were investigated in 31 surgical specimens of primary breast carcinoma. These studies utilized the polymerase chain reaction followed by restriction-fragment-length polymorphism and single-strand-conformation polymorphism analyses combined with tumor cell enrichment by cell sorting. Loss of heterozygosity at the APC locus was detected in 8 (38%) of 21 informative cases, but only 2 (6%) of 31 tumors carried a mutated APC gene. Direct DNA sequencing analysis confirmed mutations at codon 1081 (AGC to ATC) resulting in an amino acid substitution of serine for isoleucine, and at codon 1096 (CAG to CAT) resulting in a substitution of glutamine for histidine. There were no significant correlations between the loss of heterozygosity or mutation at the APC locus and any clinicopathological characteristics. Our present observations suggest that the mutations of the APC gene may play an important role in the genesis of certain breast carcinomas, and that another tumor-suppressor gene, which is the true target of frequent loss of heterozygosity, may exist near the APC gene.
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PMID:Aberrations of the APC gene in primary breast carcinoma. 779 98

Fascinating progress has been made in the past 2 years in our understanding of the genetic alterations associated with colorectal cancer predisposition and development. First, the genotype-phenotype relationship of the cancer susceptibility syndrome associated with familial adenomatous polyposis has been shown to depend on mutation type. Second, hereditary nonpolyposis colorectal cancer syndromes have been recognized as being frequently associated with a defect in the DNA mismatch-repair pathway. A gene on chromosome 2 called hMSH2, which demonstrates homology with the bacterial repair gene MutS, has been shown to be altered in some families with hereditary nonpolyposis colorectal cancer. A defect on chromosome 3 may act by impairing the same pathway. Genotyping of particular loci, termed microsatellite, provides an easy identification of tumors deficient in mismatch repair. Third, the mechanisms by which the inactivation of tumor-suppressor genes such as p53 and APC may contribute to the tumorigenic process have begun to be elucidated. These different discoveries will have important impacts in the prevention and management of colorectal carcinoma, one of the most frequent human cancers.
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PMID:Advances in the genetics and molecular biology of colorectal tumors. 780 42

beta-Catenin is involved in the formation of adherens junctions of mammalian epithelia. It interacts with the cell adhesion molecule E-cadherin and also with the tumor suppressor gene product APC, and the Drosophila homologue of beta-catenin, armadillo, mediates morphogenetic signals. We demonstrate here that E-cadherin and APC directly compete for binding to the internal, armadillo-like repeats of beta-catenin; the NH2-terminal domain of beta-catenin mediates the interaction of the alternative E-cadherin and APC complexes to the cytoskeleton by binding to alpha-catenin. Plakoglobin (gamma-catenin), which is structurally related to beta-catenin, mediates identical interactions. We thus show that the APC tumor suppressor gene product forms strikingly similar associations as found in cell junctions and suggest that beta-catenin and plakoglobin are central regulators of cell adhesion, cytoskeletal interaction, and tumor suppression.
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PMID:E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. 780 82

We investigated the frequency and clinical significance of loss of heterozygosity (LOH) at the APC, MCC, and DCC tumor suppressor gene loci in 108 cases of resected non-small cell lung cancer (NSCLC). LOH at the APC/MCC gene cluster at chromosome 5q21 occurred frequently; it affected 29% of informative NSCLC cases and correlated with a significantly worse survival (P < 0.01). Furthermore, in the subtype most frequently affected (SCC), LOH at 5q not only correlated with a worse survival but also tumor involvement of the mediastinal and/or hilar nodes. In contrast, LOH at the DCC locus at chromosome 18q was far less frequent, occurring in 14% of NSCLC cases, and it was not associated with advanced stage or prognosis. These data suggest that LOH at 5q has a role in determining tumor progression and survival in NSCLC, and may prove to be a clinically useful prognostic indicator.
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PMID:Tumor progression and loss of heterozygosity at 5q and 18q in non-small cell lung cancer. 781 47

Mutations in mammalian genomes are the result of several mutagenic processes that are intrinsic to cell metabolism. Analysis of the mutation spectrum of a chromosomal gene is a valuable tool for assessing the contribution of these mechanisms to mutagenesis in the cell. We have studied the specificity of mutations induced by various mutagens in a cDNA hprt gene integrated in a chromosome of a mouse cell line. To understand the mechanisms underlying mammalian cell mutagenesis, we compiled a list of more than 250 sequenced hprt mutations that arose spontaneously or were induced by mutagens, and compared it with the published mutation data. There are at least two distinct processes of mutagenesis in eukaryotic cells: one is mispairing, while another is errors in translesion synthesis. The alkylating agent methylnitrosourea causes G:T mispairing; consequently, most mutations it induces are G to A transitions. The second process can occur spontaneously or be caused by exposure to X-rays, Trp-P2, a tryptophan pyrolysate, or acetylaminofluorene. A variety of premutagenic lesions are produced in DNA by these mutagens, but spectra of the mutations resemble each other, especially in the high frequency of deletions at the sites of short direct repeats. The slippage--misalignment mechanism accounted well for the greater part of the observed deletions. A similar spectrum of mutations was observed in the tumor suppressor gene APC from colorectal tumors; about 40% are deletions at the sites of short repeats. These findings led us to propose that slippage--misalignment is an ubiquitous mechanism of mutagenesis and is responsible for a significant proportion of spontaneous mutations in mammalian cells.
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PMID:Slippage--misalignment: to what extent does it contribute to mammalian cell mutagenesis? 783 71

The APC gene plays a major role in human colon carcinogenesis. We determined the genomic structure of the rat Apc gene, and we analyzed mutations in colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), potent carcinogens contained in ordinary daily human food. Of eight PhIP-induced tumors, one tumor had two Apc mutations, two tumors had a mutation with loss of the normal allele, and one had a mutation. Two of the above five mutations were at nucleotide 1903, one at 2605, and two at 4237, all being a deletion of a guanine base at the 5'-GGGA-3' site and resulting in truncation of the APC protein. Of 13 IQ-induced tumors, 2 had an Apc mutation with loss of the normal allele. The two mutations were a missense mutation (T-->C) at nucleotide 1567 and a nonsense mutation (C-->T) at 2761. Alteration of the Apc gene was shown to play a more important role in PhIP-induced than in IQ-induced rat colon carcinogenesis. PhIP-induced tumors are characterized by their specific and unique mutation, which may be useful for mutational fingerprinting of human cancers.
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PMID:Specific 5'-GGGA-3'-->5'-GGA-3' mutation of the Apc gene in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 784 77

Beta-catenin is a cytosolic protein originally identified through its association with the cadherin class of cell-adhesion proteins. However, recent studies have demonstrated that there are cadherin-independent pools of beta-catenin and that beta-catenin binds at least one other protein, the product of the tumor-suppressor gene APC. Furthermore, beta-catenin is the target of two signal transduction pathways mediated by the proto-oncogenes src and wnt-1. This raises the possibility that beta-catenin plays a pivotal role in balancing cellular responses to both adhesive and proliferative signals.
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PMID:Beta-catenin: a common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways. 784 66

Colorectal carcinomas demonstrate extensive molecular genetic alterations throughout the genome. The genetic changes in cancer of the colon and rectum are among the best understood of any common human cancer. The genetic abnormalities include both dominant-acting oncogenes (Ki-ras, c-src) and tumor-suppressor genes which undergo inactivation or loss (APC, DCC, p53). The evolution of the cancer is a complicated and multistep process. At the various steps of this phenomenon we can recognize specific molecular genetic alterations. These particular genetic changes may be useful as improved markers to predict those patients who have an aggressive cancer of the colon, with occult metastases or increased metastatic capability and this selection of patients could lead to improved surgical and medical management.
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PMID:The genetic basis of colorectal cancer--clinical implications. 785 69

Cell fusion experiments performed by Harris et al. informed that tumor suppressor genes are inactivated in malignant cells. Inactivation of tumor suppressor genes induced by genetic alteration such as point mutation and deletion leads to disturbance in the control of cell proliferation resulting in deregulated growth of normal cells. Recently, many challenges of scientists including clinicians trying to direct the studies of tumor suppressors toward cancer therapy have been stimulated. For that purpose, it is important to understand the molecular mechanism in which change of normal phenotypes into tumor take place. In this review, recent topics on tumor suppressors such as Rb, p53, Wt1, APC, NF1, s-Myc and H19 are included to discuss their significance and function.
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PMID:[Tumor suppressor genes]. 785 29

Mutations or loss of the APC tumor-suppressor gene is important for the development of colorectal polyps and cancers, but little is known about the function of this gene in normal tissue. To study the role of APC and other genes in colonocytes in vivo, a system was developed whereby transient expression of genes is established in normal rodent colonic epithelium, using liposomal gene delivery by rectal catheter infusion. Expression of a beta-galactosidase reporter gene and of the human APC gene under a constitutive promoter is demonstrated. A high efficiency of transfection is maintained, with close to 100% of epithelial cells expressing the introduced gene. Expression is transient and does not persist beyond 4 days, consistent with the normal turnover time of gut epithelium, but it can be maintained by repeated treatments. Human APC was expressed for three weeks under these conditions at approximately one-tenth the level of the endogenous APC gene, and no toxicity was observed beyond that attributed to repeated rectal enemas. These results reveal that in vivo expression of exogenous gene is feasible using a liposomal delivery system and suggest a method to further study the physiologic role of APC or other genes in the interrelated process of colonic epithelial proliferation and differentiation.
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PMID:Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery. 787 18


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