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Results for “Genes, APC”

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PubMed2002

Mutation analysis of APC gene in gastric cancer with microsatellite instability.

AIM: To evaluate the role of APC mutation in gastric carcinogenesis and to correlate APC mutation with microsatellite instability (MSI) in gastric carcinomas. METHODS: APC mutation was measured with multiplex PCR, denaturing gradient gel electrophoresis and DNA sequencing; and MSI was analyzed by PCR-based methods. RESULTS: Sixty-eight cases of sporadic gastric carcinoma were studied for APC mutation at exon 15 and MSI. APC mutations were detected in 15(22.1 %) gastric cancers. Frequence of APC mutation (33.3 %) in intestinal type of gastric cancer was significantly higher than that in diffuse type (13.1 %, P<0.05). On the contrary, no association was observed between APC mutation and tumor size, differentiation, depth of invasion, metastasis or clinical stages. Using five microsatellite markers, MSI in at least one locus was detected in 17 of 68 (25 %) of the tumors analyzed. APC mutations were all detected in MSI-L (only one locus, n=9) or MSS(tumor lacking MSI or stable, n=51), but no mutation was found in MSI-H (> or =2 loci, n=8). CONCLUSION: APC mutation is involved in carcinogenesis of intestinal type of gastric cancer and is independent of MSI phenotype but related to the LOH pathway in gastric cancer.

Adenomatous Polyposis Coli Protein↗

PubMed1989

Linkage analysis in familial adenomatous polyposis: order of C11P11 (D5S71) and pi 227 (D5S37) loci at the apc gene.

Linkage analysis with DNA probes C11P11 and pi 227 is reported in six Scottish families with familial adenomatous polyposis. Two families were informative for C11P11 and all six were at least partly informative for pi 227. Two C11P11-apc and two pi 227-apc recombinants were identified and one of these was recombinant for both C11P11-apc and pi 227-apc. A further possible combined C11P11-apc and pi 227-apc recombination event was also identified. Peak lod score for linkage of C11P11 to apc was 5.80 at a recombination fraction (theta) of 0.069 (95% probability limits 0.012-0.191) and for linkage of pi 227 to apc was 3.19 at theta = 0.110 (95% probability limits 0.023-0.286). Peak lod score for linkage of C11P11 to pi 227 was 1.79 at theta = 0.00. The data support a gene order of pi 227-C11P11-apc.

Chromosomes, Human, Pair 5↗

PubMed1995

Radioimmunoassay of the APC gene product using antibodies against its middle and carboxyl regions.

A radioimmunoassay (RIA) has been developed for the adenomatous polyposis coli protein (APC). High-avidity rabbit polyclonal antibodies were produced against synthetic peptides corresponding to amino acids 1865-1881 (APC-1) and to amino acids 1336-1350 (APC-2) in APC's 2844 amino acid sequence. Both antibodies were utilized in RIA to evaluate full-length APC that is present in the insoluble particulate fraction of cell lysates. High salt extraction, often employed for coiled-coil type protein preparations, was found to be useful for extraction of APC from lysates of normal colonic epithelium. Proteolytic digestion of high salt extracts increased antibody reactivity toward both epitopes, suggesting that APC-1 and APC-2 antigenic sites are partially concealed due to APC's involvement in multiprotein complexes. Thus, RIA using our antibodies will provide a valuable tool for APC protein purification and in studies for elucidating APC's biologic function.

Adenomatous Polyposis Coli Protein↗

PubMed2000

Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study.

Papillary thyroid carcinoma (PTC) is one extracolonic manifestation affecting about 1-2% of patients with familial adenomatous polyposis (FAP). Ninety-seven patients with FAP-associated PTC have previously been reported, including 6 pairs of siblings. During a European collaborative study, 15 patients with FAP-associated PTC were collected. All 15 patients were females. The mean age at thyroidectomy was 24.9 yr (range, 19-39 yr). In 13 subjects, APC germline mutations had been detected; they were at codons 140, 593, 778, 976, 993, 1061 (n = 5), 1105 (n = 1), and 1309 (n = 2), respectively. A review of the literature added 11 other patients with FAP-associated PTC and detection of germline APC mutations; they were at codons 313 (n = 2), 698 (n = 3), 848 (n = 2), 1209 (n = 2), 1061 (n = 1), and 1105 (n = 1), respectively. The latter led to formation of the same stop codon (TAA) at 1125-1126 as the mutation at codon 1061. Therefore, 21 of 24 mutations were in exon 15 in the genomic area usually associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), i.e. codons 463-1387. Typical CHRPE was found in 17 of 18 affected patients who had specific screening. Interestingly, 22 of the 24 patients had their mutation out of the mutation cluster region (codons 1286-1513), which is currently considered the hot spot mutation area, in particular for extracolonic manifestations of FAP. The difference in the incidence of germline mutations before and after codon 1220 between PTC and non-PTC FAP patients was statistically significant (P<0.05) for both patients and kindreds (P = 0.005 and P = 0.049, respectively). Even if most mutations were scattered throughout the entire 5'-portion of exon 15, 8 of 23 patients (6 with mutation at 1061 and 2 with mutation at 1105; i.e. more than one third) had the same truncated protein product. The awareness that patients with PTC usually have APC mutations that cluster in a well defined genomic area, in addition to giving a deeper insight into gene function, could facilitate both earlier diagnosis and better treatment. In particular, intensive screening for thyroid nodules after age 15 yr is recommended when a single patient or an entire kindred have CHRPE and/or mutations in the 5'-portion of exon 15.

Adenomatous Polyposis Coli↗

PubMed1995

The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase.

The APC gene is mutated in familial adenomatous polyposis (FAP) as well as in sporadic colorectal tumours. The product of the APC gene is a 300 kDa cytoplasmic protein associated with the adherence junction protein catenin. Here we show that overexpression of APC blocks serum-induced cell cycle progression from G0/G1 to the S phase. Mutant APCs identified in FAP and/or colorectal tumours were less inhibitory and partially obstructed the activity of the normal APC. The cell-cycle blocking activity of APC was alleviated by the overexpression of cyclin E/CDK2 or cyclin D1/CDK4. Consistent with this result, kinase activity of CDK2 was significantly down-regulated in cells overexpressing APC although its synthesis remained unchanged, while CDK4 activity was barely affected. These results suggest that APC may play a role in the regulation of the cell cycle by negatively modulating the activity of cyclin-CDK complexes.

3T3 Cells↗

PubMed1994

Abnormalities of the adenomatous polyposis coli gene in human oral squamous-cell carcinoma.

Recent studies have suggested that abnormalities in the adenomatous polyposis coli gene (APC gene) are associated with the development not only of familial adenomatous polyposis coli (FAP) but also of cancers in digestive organs. In order to elucidate whether abnormalities of the APC gene could contribute to the development of oral squamous-cell carcinoma (SCC), genomic DNAs from tumors and normal tissues of 24 unrelated Japanese patients were examined by using PCR-SSCP (polymerase chain reaction single-strand conformation polymorphism) and sequence analyses. Five novel nucleotide substitutions of the APC gene in tumor tissues were identified in 3 patients with oral SCC (12.5%), resulting in 3 amino-acid replacements or a truncation of the APC gene product. We also examined 24 tumor and 24 normal tissue samples for loss of heterozygosity (LOH) at exon 11 of the APC gene by PCR-LOH assay. In this analysis, 45.8% of samples were informative and LOH was detected in 72.7% of informative cases. The frequency of LOH in oral SCC was similar to that previously reported in esophageal SCC. These results suggest that abnormalities in the APC gene are associated with the development of human oral SCC.

Base Sequence↗

PubMed1993

Simple, rapid, and accurate determination of deletion mutations by automated DNA sequencing of heteroduplex fragments of the adenomatous polyposis coli (APC) gene generated by PCR amplification.

Germline mutations in patients with familial adenomatous polyposis were analyzed by polymerase chain reaction (PCR) amplification of the adenomatous polyposis coli gene. PCR products from heterozygous patients for deletions of this gene formed four distinct bands on polyacrylamide gel electrophoresis. The four fragments were subsequently purified and both strands of each fragment were directly sequenced, using an automated DNA sequencer and the same primers as those for PCR amplification. It was found that the two slower migrating fragments were "bulge" heteroduplexes, while the other two were homoduplexes made up of two wild-type strands and two deletion-mutant strands, respectively. The sites of deletions in the adenomatous polyposis coli gene could be exactly determined in four of the five patients. In an attempt to identify deletion-carriers of familial adenomatous polyposis at the presymptomatic stage, a family study was also carried out, and two children were found to have the same mutations as those of their affected parents. The direct sequencing of heteroduplex fragments generated during PCR amplification is a potentially useful method for detecting mutations of not only the adenomatous polyposis coli gene but also many other genes of genetic diseases.

Adenomatous Polyposis Coli↗

PubMed1998