Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genes, APC”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1995

[The distribution of tumor suppressor gene APC mRNA in guinea pig brain].

The APC gene was identified in 1991 at chromosome 5 q 21, which is responsible for the familial adenomatous polyposis (FAP). The gene has been classified as one of the tumor suppressor genes. The APC gene mutations were suggested to initiate sporadic as well as inherited colorectal neoplasia and to be related to mental retardation. The different forms of APC gene expression and their association to carcinogenesis have been carefully studied. However, the function of APC gene in the central nervous system has not been known. In this study, on the basis of the cDNA cloning of APC homologue in the guinea pig by Dr. Fan Meng, we rescued this fragment including the full length encoding region from plasmid pMe 18s and then subcloned it into the polylink site of the plasmid pBluscript KS. Both digoxigenin labeled sense and anti-sense RNA were synthesized by in vitro transcription. RNase protection assay and in situ hybridization enable us to examine the distribution of APC transcripts in guinea pig brain. Strong signals were detected in hippocampus. APC mRNA was mainly localized in the pyramidal neurons of CA 1, CA 3, as well as in the dentate granule cells; the cerebellum granular cells also showed strong staining; in the cerebrum, the parietal and primary olfactory cortex showed stronger signals than the frontal cortex; in olfactory bulb, positive cells with strong signals were observed: the brain stem showed a relatively weaker staining. Very similar expression pattern was also shown in embryonic guinea pig brain; except that the expression of APC gene in frontal cortex and olfactory bulb was stronger than that in adult animals. The results suggest that the APC transcripts in brain may play an important role during the early development of the central nervous system. Further study may enable us to take a deeper insight into the mechanism underlying inherited mental deficiency.

Animals↗
PubMed1994

High levels of expression of the tumor suppressor gene APC during development of the rat central nervous system.

The adenomatous polyposis coli (APC) gene is a tumor suppressor gene that is mutated in human familial adenomatous polyposis, an autosomal dominant condition with predisposition to colorectal carcinoma and brain tumors. Although tumor suppressor genes appear to play a general role in regulating cellular proliferation, the normal biological function of the APC gene product is unknown. In the present study, we cloned fragments of the rat homolog of the APC gene and examined its tissue distribution by Northern blot analysis. These studies demonstrated particularly high levels of APC mRNA in brain. To gain clues to the role of the APC gene in brain function, we examined the neuroanatomical distribution of APC mRNA using in situ hybridization. In the adult, prominent expression of APC mRNA was observed in the olfactory bulb, hippocampus, and cerebellum, with low levels of hybridization in other regions of adult rat brain. In contrast, during embryonic and early postnatal development (1-2 weeks), high levels of APC expression were found throughout the brain and then decreased to adult levels by 6 weeks after birth, except in the olfactory bulb where the high levels of APC mRNA found in development persist in the adult. During development of cortex, cerebellum, and retina, APC mRNA expression was particularly prominent in layers containing newly formed postmitotic neurons, with lower levels observed in the proliferative zones where neurogenesis occurs. The high levels of APC expression from early neurogenesis until late stages of neuronal maturation suggest that APC may contribute to suppressing neuronal proliferation during this period of intense growth.

Adenomatous Polyposis Coli↗
PubMed2003

[The I1307K mutation and protein expression of APC gene in gastric cancer].

In order to explore the correlation of the abnormalities of tumor suppressor gene APC with the carcinogenesis and progression of gastric cancer. The I1307K mutation of APC gene in gastric cancer was analysed using Amplification Refractory Mutation System PCR(ARMS ,PCR),also the expression of APC protein in gastric cancer of different stages was detected by immunohistochemical method. We found that there wasn't I1307K mutation of APC gene in 62 cases of blood samples of susceptible population in high incidence areas of gastric cancer and 45 cases of gastric cancer tissues. The positive rates of APC protein in gastric cancer (both early and progressive gastric cancer) were significantly lower than that in normal mucosa,the positive rates of APC protein in progressive gastric cancer were significantly lower than that in early gastric cancer,the positive rates of APC protein in gastric cancer with lymph node metastasis were significantly lower than that in gastric cancer without lymph node metastasis. So it was thought that there might be no correlation between the I1307K mutation of APC gene and carcinogenesis of gastric cancer in China,but the decreased expression of APC protein was closely related to the carcinogenesis,progression and lymph node metastasis of gastric cancer.

English Abstract↗
PubMed2000

A novel non-pathogenetic polymorphism of the APC gene in a patient with familial adenomatous polyposis coli.

DISORDER: Familial adenomatous polyposis coli. ETHNICITY OF PATIENT: Japanese. GENE: APC. GENBANK ACCESSION NUMBER: M 74088. CHROMOSOMAL ASSIGNMENT: 5q21. TYPE OF DNA VARIANT: A germline missense mutation. A germline nonsense mutation. MUTATION: CGG (Arg, wild type) to TGG (Trp) substitution at codon 88 in exon 3 of the APC gene. CGA (Arg, wild type) to TGA (term.) at codon 213 in exon 5 of the APC gene. ALLELIC FREQUENCY: <0.014 (missense mutation, TGG at codon 88). METHOD OF MUTATION DETECTION: PCR-SSCP/direct sequencing.

Adenomatous Polyposis Coli↗
PubMed2000

A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor.

Desmoid tumors arise sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis (FAP). In FAP, two distinct clinical presentations of the desmoid phenotype are seen: 1) one or a few desmoid tumors present predominantly in the abdominal wall or the abdomen; 2) a florid proliferation of tumors early in life, mostly near the axial skeleton or extremities. These different phenotypes have been associated with different sites of germline mutations in the adenomatous polyposis coli gene (APC gene). We present a large, French-Canadian kindred with a florid desmoid tumor phenotype caused by a germline mutation at codon 2643-2644 of the APC gene. The phenotype was characterized by the early onset of multiple tumors, arising near the axial skeleton and in proximal extremities. The penetrance of desmoid tumors was near 100% in this kindred. However, the expression of the disease was variable amongst the different affected relatives. Many gene carriers had cutaneous cysts. Polyposis of the colon was rarely observed in the affected individuals and we did not document upper gastro-intestinal polyps. The mutant APC allele did not express a stable truncated protein in vivo. Molecular analysis of the proband's tumor DNA revealed a somatic inactivating mutation of the wild-type allele. Immunohistochemistry on the tumor also demonstrated elevated levels of beta-catenin. The present study demonstrates that this extreme 3' APC mutation is associated with a severely penetrant desmoid phenotype and attenuated polyposis coli. It also suggests the involvement of the beta-catenin pathway in the development of desmoid tumors in FAP. The natural history of the disease is variable between individuals, and surgical interventions have to be timed appropriately due to the frequent recurrences.

3' Untranslated Regions↗
PubMed1996

[The APC gene].

The tumor suppressor gene APC is mutated in most cases of familial adenomatous polyposis (FAP) and sporadic colorectal tumors. The product of the APC gene is a 300 kDa protein present in the cytoplasm as a homodimer. Interestingly, the APC protein is known to interact with the adherence junction protein catenin, suggesting that APC may be involved in cell adhesion. More recently we have demonstrated that overexpression of APC blocks cell cycle progression from the G0/G1 to the S phase.

Adenomatous Polyposis Coli↗
PubMed1999

Germline and somatic mutations in exon 15 of the APC gene and K-ras mutations in duodenal adenomas in patients with familial adenomatous polyposis.

BACKGROUND: In sporadic colorectal adenomas mutations in the adenomatous polyposis gene (APC) are among the first gene aberrations to appear. In familial adenomatous polyposis (FAP) the patients already have a germline mutation in the APC gene. To investigate the natural history of duodenal adenomas in FAP patients, we examined germline and somatic mutations of the APC gene and K-ras mutations in these lesions. METHODS: Frozen sections from 54 duodenal polyps from 31 FAP patients were used to histologically verify the presence of adenomatous growth in the mucosa; the rest of each biopsy specimen was processed for DNA extraction. APC exon 15 was investigated with the protein truncation test (PTT), using four overlapping polymerase chain reaction (PCR) fragments, and samples showing an APC mutation were thereafter sequenced. The adenomas were examined for K-ras mutations by use of a combination of the 'enriched PCR method' and temporal temperature gradient electrophoresis. RESULTS: APC germline mutations in exon 15 were found in 19 of 31 (61%) patients, whereas somatic mutations were localized to 12 of 54 (22%) duodenal adenomas. In seven adenomas both the germline and the somatic mutations were found, whereas five small adenomas showed somatic mutations only. There was no tendency for more mutations to be detected in large and severely dysplastic adenomas compared with small and mildly dysplastic ones. K-ras mutations were found in four (7%) duodenal adenomas. CONCLUSIONS: The low rate of somatic APC and K-ras mutations in duodenal adenomas may indicate another neoplastic pathway than in FAP adenomas of the large bowel, or that a modifier gene is cosegregating with the disease.

Adenoma↗
PubMed1992

Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene.

We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients. In addition to loss of heterozygosity (LOH) at the APC locus in 30 tumors, 43 other somatic mutations were detected. Twenty-one of them were point mutations; 16 nonsense and two missense mutations, and three occurred in introns at the splicing site. Twenty-two tumors had frameshift mutations due to deletion or insertion; nineteen of them were deletions of one to 31 bp and three were a 1-bp insertion. One tumor had a 1-bp deletion in an intron near the splicing site. Hence, 41 (95%) of 43 mutations resulted in truncation of the APC protein. Over 60% of the somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region), which accounted for less than 10% of the coding region. Combining these data and the results of LOH, more than 80% of tumors (14 adenomas and 39 carcinomas) had at least one mutation in the APC gene, of which more than 60% (9 adenomas and 23 carcinomas) had two mutations. These results strongly suggest that somatic mutations of the APC gene are associated with development of a great majority of colorectal tumors.

Adenoma↗
PubMed2001

Studies on human colon cancer gene APC by targeted expression in Drosophila.

Mutations in human Adenomatous Polyposis Coli (APC) gene are associated with both familial and sporadic colorectal tumors. APC is known to down regulate beta-catenin levels, a transducer of Wnt signaling. The aim of this study is to provide transgenic Drosophila expressing either full-length or truncated forms of human APC (hAPC) protein and methods for using them in functional genomics and drug screening. Consistent with its biochemical properties, targeted expression of either full-length hAPC or its beta-catenin binding domain alone negatively regulated the function of the beta-catenin homologue, Armadillo (Arm) and thereby, inhibited Wnt/Wg signaling during fly development. hAPC inhibited Arm function even in the absence of GSK-3beta activity, although the latter was required to mediate the degradation of Arm. Consistent with this, hAPC suppressed the phenotypes induced by the over-expression of degradation-resistant forms of Arm. Subsequently, using hAPC-induced eye phenotypes as the assay in a suppressor-enhancer screen, we have identified two new loci in Drosophila, which modulate Wnt/Wg signaling. In addition, an anti-colon cancer drug, indomethacin, specifically enhanced hAPC-induced phenotypes.

Adenomatous Polyposis Coli Protein↗
PubMed1997

Alternative splicing of the APC gene and its association with terminal differentiation.

The human tumor suppressor gene, APC, is composed of at least 21 exons, 7 of which are alternatively expressed. Sixteen APC transcripts that differ in their 5'-most regions and arise by the alternative inclusion of 6 of these exons have been identified by reverse transcription-PCR analysis of RNA prepared from human, mouse, and rat cell lines and tissues. Tissue-specific differences were observed in the expression of APC transcripts without exon 1, a coding region for a heptad repeat that supports APC homodimerization. Transcripts without exon 1 were observed at high levels in postmitotic, differentiated tissues and in two cell lines following the induction of differentiation. Sequence analysis of these novel open reading frames predicts APC proteins with different amino-terminal domains and therefore potentially different abilities to associate with other proteins. Our findings suggest that the alternative splicing of APC leads to alternative forms of APC proteins with potentially unique functions in growth control and differentiation.

Alternative Splicing↗
PubMed1994

Association of APC gene mutations and histological characteristics of colorectal adenomas.

Fifty-nine colonic adenomas and 6 hyperplastic colonic polyps were analyzed by single-strand conformation polymorphism analysis for mutations in the adenomatous polyposis coli gene (APC). Frameshifts and premature stop codons in at least one copy of APC were detected in 25 of these adenomas. Five adenomas carried 2 APC mutations. No mutations in APC were found in any of the 6 hyperplastic polyps. The detection of APC mutations increased with size and degree of dysplasia and in rectal as compared to colonic adenomas, although the association was not statistically significant. The frequency of detectable APC mutations was higher in tubulovillous and villous adenomas (10 of 13) than in tubular adenomas (15 of 45) (odds ratio, 6.67; 95% confidence limits, 1.39-41.83; P = 0.005). The significance of the association between the detection of APC mutations and a villous architecture was confirmed in multivariate analysis (relative risk, 6.67; 95% confidence limits, 1.54-28.8; P = 0.005). In conclusion, APC mutation plays a role in adenoma progression; its frequency is significantly higher in lesions with a more villous morphology.

Adenoma, Villous↗
PubMed2004

Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene.

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, the relevance of rare exonic single-base substitutions at nucleotide positions close to splice sites that are predicted to result in missense or silent (SNP) variants or substitutions in introns at splice-site positions that are not highly conserved has not been systematically examined in FAP patients. In 34 index patients, we identified 26 different heterozygous single-base substitutions at or close to the splice sites. We characterized five exonic mutations in exon 4 (c.423G>T), exon 14 (c.1956C>T, c.1957A>G, and c.1957A>C), and exon 15 (c.1959G>A) by transcript analysis and by splice-prediction programs (BDGP, SpliceSiteFinder, and ESEfinder). The splicing patterns of these variants were compared to those of 16 different substitutions at highly or less-conserved intronic splice-site positions, and to normal controls. In addition, we analyzed cosegregation of the variants with affected family members and examined the genotype-phenotype correlation. We could demonstrate that the four unclear variants in exon 4 and 14 that are predicted to result in missense or silent mutations in fact lead to complete exon skipping due to aberrant splicing; one possible explanation for this observed effect might be the disruption of exonic splicing enhancer (ESE) motifs. In contrast, the substitution at the first position of exon 15 seems to actually be a silent variant. We present the first systematic evaluation of different single-base substitutions in APC at or close to splice sites at transcript level. We show that the consequence of exonic mutations cannot be evaluated only by the predicted change in amino acid sequence but rather by the change at DNA level. The functional analysis of variants with unknown pathogenic effect plays an important role in increasing the mutation detection rate and achieving validation of predictive testing.

Adenomatous Polyposis Coli↗
PubMed2004

Genetic and epigenetic alterations of the APC gene in malignant melanoma.

High levels of beta-catenin and activating mutations in the beta-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic beta-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on beta-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity.

Adenomatous Polyposis Coli Protein↗
PubMed2002

A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.

Adenomatous Polyposis Coli↗
PubMed2002

Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas.

Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.

Adenoma↗
PubMed2000

[From gene to disease; the APC gene and familial adenomatous polyposis coli].

Familial adenomatous polyposis coli is an autosomal dominant hereditary form of colorectal cancer associated with mutations in the adenomatous polyposis coli (APC) gene on chromosome 5. The APC protein is thought to mediate the stability of beta-catenin in the WNT signaling transduction pathway ('wingless-type mouse mammary tumor virus integration site family member') in normal colonic epithelial cells, thereby indirectly regulating the expression of WNT target genes such as the c-myc-oncogene. APC gene mutations cause the development of multiple adenomatous polyps in the colorectum, which strongly predisposes gene carriers to colorectal cancer. Extracolonic manifestations, including gastric and duodenal polyps, osteomas, desmoids, epidermoid cysts, and retinal lesions, are commonly observed in patients with familial adenomatous polyposis. Detection of mutations in the APC gene allows genetic counselling and reliable identification of at-risk individuals.

Adenomatous Polyposis Coli↗
PubMed2001

Genetic analysis of the APC gene regions involved in attenuated APC phenotype in Israeli patients with early onset and familial colorectal cancer.

The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1-5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron 5 was detected in 16 individuals, 8 patients were carriers of the 11307K variant, a mutation prevalent among Jewish individuals with colorectal cancer, and 4 displayed the E1317Q variant. We conclude that in Israeli individuals with early onset or familial CRC, truncating mutations in the APC gene regions associated with attenuated APC phenotype probably contribute little to disease pathogenesis.

Adult↗
PubMed1995

Evidence for a novel exon in the coding region of the adenomatous polyposis coli (APC) gene.

Germline mutations of the tumor suppressor gene APC cause familial adenomatous polyposis. Somatic APC alterations are involved in several sporadic neoplasms, including colorectal, duodenal, gastric, and esophageal carcinoma. The APC mRNA is encoded by 15 exons. Additional transcripts have been reported, due to alternative splicing of coding as well as noncoding regions. Two mRNA isoforms occur due to a deletion of exon 7 or a partial deletion of exon 9. We have identified a novel exon, flanked by APC exons 10 and 11, which is expressed as an alternatively transcribed product of the gene. Further, we have shown that the novel exon consists of a heptad repeat motif and is conserved across species.

Adenomatous Polyposis Coli↗