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PubMed2005

Mutation spectrum of the APC gene in 83 Korean FAP families.

Familial adenomatous polyposis (FAP) is a clinically well-defined hereditary disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is characterized by polyposis in the large bowel and variable extracolonic manifestations. With an increase of reported APC germline mutations, many reports have investigated genotype-phenotype correlations in FAP patients. Here, we analyzed the APC gene for germline mutations in 83 unrelated Korean FAP patients and investigated genotype-phenotype correlations. We identified germline APC mutations in 59 (71%) of the cases, including 34 frameshift mutations, 19 nonsense mutations, and six splice site mutations. Among 59 patients with the identified germline mutation of the APC gene, 37 had been reported previously and were included in the genotype-phenotype analysis. In the other 22 patients, we identified seven novel mutations: c.1438C>T, c.2232_2233dupCT, c.3426delT, c.3739_3769del31, c.3931_3935delATTGG, c.4332dupA, and c.4722_4725delACTA. Desmoid tumors were identified in six of the examined FAP patients, five of whom had APC germline mutations; these mutations involved codons 849, 864, 1309, 1444 and 1464, respectively (c.2547_2548delTA, c.2592_2593insCT, c.3927_3931delAAAGA, c.4332dupA and c.4391-4394delAGAG). Four of the included FAP patients had papillary thyroid cancers; all were female and had germline APC mutations (c.1863_1865delTTAincCT, c.2805C>A, c.3183_3187delACAAA and c.3927_3931delAAAGA).

Adenomatous Polyposis Coli↗
PubMed1994

Presymptomatic diagnosis in families with adenomatous polyposis using highly polymorphic dinucleotide CA repeat markers flanking the APC gene.

A panel of five multiallelic and highly informative dinucleotide CA repeat markers flanking the APC gene was used for presymptomatic diagnosis of familial adenomatous polyposis coli (FAP). Marker regions were amplified by PCR. DNA fragments were separated by electrophoresis in denaturing polyacrylamide gels and visualised by ethidium bromide staining. Two or more markers were found to be informative in all nine families tested, and all 23 persons at risk could be diagnosed as affected or unaffected by the disease gene, the probability being > 99.9% in 14 cases from six families in which flanking markers were informative. We found no indication for locus heterogeneity of the disease in our sample. The polyposis phenotype and its extracolonic manifestations co-segregated with a distinct haplotype determined by the markers flanking the APC gene. In one family with no remaining living affected members, we could infer the high risk haplotype from genotyping of first degree relatives. The segregation of this haplotype is consistent with the occurrence of CHRPEs in the progeny. In a sporadic case we made use of the typical early extracolonic manifestations of the disease (osteomas, desmoids) to identify the high risk haplotype. We conclude from our experience that indirect genotyping of FAP with this particular panel of closely linked and highly polymorphic microsatellite markers is a rapid, efficient, and highly reliable method for presymptomatic diagnosis of FAP.

Adenomatous Polyposis Coli↗
PubMed2005

[Detection of germline mutations in the APC gene with the protein truncation test].

The protein truncation test was established for analyzing mutations in the adenomatous polyposis coli (APC) gene which plays an important role in familial adenomatous polyposis (FAP). The sites of APC mutations and the clinic features of FAP patients were examined to find the relationship between them. Genomic DNA, which was extracted from peripheral blood lymphocytes of 22 FAP patients and the normal colon tissues of 43 sporadic colorectal cancers, were examined for mutations in exon15 of the APC gene by using PCR-TNT T7 Quick Coupled Tanscription/Translation System. The subsequent sequencing was used to confirm the mutation sites. Germline mutations were found in 5 of 22 FAP patients. All of the five mutations showed base pair deletions and led to produce truncated protein. No truncating germline mutation was found in normal tissues of 43 sporadic colorectal cancers. The protein truncation test is a sensitive and accurate technique to detect truncated mutations especially in the large exons of APC gene. It can be used as an routine method for assisting the early diagnosis of the FAP patients.

Adenomatous Polyposis Coli↗
PubMed1997

Detection of heterozygous truncating mutations in the BRCA1 and APC genes by using a rapid screening assay in yeast.

The detection of inactivating mutations in tumor suppressor genes is critical to their characterization, as well as to the development of diagnostic testing. Most approaches for mutational screening of germ-line specimens are complicated by the fact that mutations are heterozygous and that missense mutations are difficult to interpret in the absence of information about protein function. We describe a novel method using Saccharomyces cerevisiae for detecting protein-truncating mutations in any gene of interest. The PCR-amplified coding sequence is inserted by homologous recombination into a yeast URA3 fusion protein, and transformants are assayed for growth in the absence of uracil. The high efficiency of homologous recombination in yeast ensures that both alleles are represented among transformants and achieves separation of alleles, which facilitates subsequent nucleotide sequencing of the mutated transcript. The specificity of translational initiation of the URA3 gene leads to minimal enzymatic activity in transformants harboring an inserted stop codon, and hence to reliable distinction between specimens with wild-type alleles and those with a heterozygous truncating mutation. This yeast-based stop codon assay accurately detects heterozygous truncating mutations in the BRCA1 gene in patients with early onset of breast cancer and in the APC gene in patients with familial adenomatous polyposis. This approach offers a rapid and reliable method for genetic diagnosis in individuals at high risk for germ-line mutations in cancer susceptibility genes.

Base Sequence↗
PubMed1997

The use and interpretation of commercial APC gene testing for familial adenomatous polyposis.

BACKGROUND: The use of commercially available tests for genes linked to familial cancer has aroused concern about the impact of these tests on patients. Familial adenomatous polyposis is an autosomal dominant disease caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene that causes colorectal cancer if prophylactic colectomy is not performed. We evaluated the clinical use of commercial APC gene testing. METHODS: We assessed indications for APC gene testing, whether informed consent was obtained and genetic counseling was offered before testing, and the interpretation of the results through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995. RESULTS: Of the 177 patients tested, 83.0 percent had clinical features of familial adenomatous polyposis or were at risk for the disease-both valid indications for being tested. The appropriate strategy for presymptomatic testing was used in 79.4 percent (50 of 63 patients). Only 18.6 percent (33 of 177) received genetic counseling before the test, and only 16.9 percent (28 of 166) provided written informed consent. In 31.6 percent of the cases the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3 percent (1 of 44). CONCLUSIONS: Patients who underwent genetic tests for familial adenomatous polyposis often received inadequate counseling and would have been given incorrectly interpreted results. Physicians should be prepared to offer genetic counseling if they order genetic tests.

Adenomatous Polyposis Coli↗
PubMed2004

Intron 4 mutation in APC gene results in splice defect and attenuated FAP phenotype.

The adenomatous polyposis coli (APC) protein is a tumor suppressor frequently involved in the development of inherited and sporadic colon cancers. Somatic mutations of the APC gene are found in 80% of all colon cancers. Inherited mutations result in familial adenomatous polyposis (FAP) as well as an attenuated form of this syndrome. FAP is characterized by the early age onset of hundreds to thousands of colonic adenomatous polyps and a virtual certainty of colon cancer unless the colon is removed. The attenuated form of FAP (AFAP) is characterized by fewer adenomas, later onset of adenomas and cancer, and a decreased lifetime cancer risk. We report a 37-year-old man with a history of more than 50 colonic adenomatous polyps, located predominately in the right colon. An insertion of a single thymidine between the second and third base pairs of intron 4 of the APC gene was identified (c.531+2_531+3insT). Monoallelic hybrid cells harboring a single copy of human chromosome 5 were generated from patient lymphoblasts. Sequencing of the APC cDNA product from these cells revealed a single RNA transcript with aberrant splicing in the mutant mRNA whereby exon 4 is deleted. The translational reading frame is shifted after codon 140 and a translational stop is generated predicting a truncated protein of 147 amino acids, thus indicating that the intronic mutation is disease causing. The lack of a secondary transcript from the mutant allele suggests that incomplete exon skipping is not the molecular mechanism behind the attenuated phenotype.

Adenomatous Polyposis Coli↗
PubMed1996

Immunochemical identification of novel high-molecular-weight protein isoforms of the adenomatous polyposis coli (APC) gene.

Mapping analyses of monoclonal antibodies (MAbs) directed against the amino-terminus of the adenomatous polyposis coli (APC) gene product revealed that epitopes recognized by the MAbs FE9, CF11 and AC4 constitute different peptide sequences encoded by the APC exons 1, 2 and 3, respectively. The protein pattern detected with these specificity-defined immunoreagents, however, differed depending on the particular antibody used on Western blots of cellular urea extracts. APC exon 15-positive "classic" p300apc polypeptide chains were identified by the MAb FE9, MAb CF11 and the C-terminus-specific MAb IE1, but only weak signals were obtained with the AC4 MAb, which defines an exon 3-encoded epitope. In contrast with this immunoreactivity, 2 novel high m.w. products of approx. 150/160 and 200 kDa were exclusively recognized by the AC4 MAb, which was shown to bind to the APC exon 3-encoded peptide sequence SRESTGYL. A molecular form of some 400 kDa was identified to represent a disulfide-bound oligomer of the p150/160apc molecules. The novel APC-related molecules did not contain exon 1- and exon 15-encoded epitopes, as confirmed with the help of the FE9 and IE1 MAbs, respectively. This observation was corroborated by the fact that these novel proteins were not truncated in a collection of familial adenomatous polyposis patients with stop mutations in exon 15. We conclude, that APC MAb AC4-reactive p150/160 and p200 polypeptide chains represent novel genuine products of the APC gene devoid of exon 1- and exon 15-encoded protein interaction domains.

Adenomatous Polyposis Coli Protein↗
PubMed2002

Pathogenic mutations and rare variants of the APC gene identified in 75 Belgian patients with familial adenomatous polyposis by fluorescent enzymatic mutation detection (EMD).

Familial adenomatous polyposis (FAP) is a dominant inherited colorectal cancer syndrome which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Enzymatic mutation detection (EMD) has potential advantages over the standard protein truncation test (PTT) that is currently used in screening the APC gene for mutations. First we wanted to validate the EMD technique in comparison to PTT. Secondly, we wanted to develop an efficient working protocol for EMD screening of APC. Seventy-five unrelated patients were screened for mutations. All mutations that had previously been detected by PTT were also identified by EMD; the sizes of the cleavage fragments were as expected according to the position of the mutations within the amplicons. A new screening strategy based on EMD allows the analysis of the APC gene in 31 overlapping PCR fragments. In total, EMD efficiently detected the 26 truncating mutations in this series. In addition, two rare variants were also detected: the first is the typical Ashkenazi missense mutation I1307K while the second variant, E1317Q, has been identifed in Belgian patients and controls, and should no longer be considered as a pathogenic mutation, but rather classified as a polymorphism.

Adenomatous Polyposis Coli↗
PubMed1992

Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients.

Recently we have isolated the adenomatous polyposis coli (APC) gene which causes familial adenomatous polyposis (FAP), and its germ-line mutations in a substantial number of FAP patients have been identified. On the basis of this information, we compared the location of germ-line mutations in the APC gene in 22 unrelated patients (12 of whom have been reported previously) with the number of colorectal polyps developed in FAP patients; 17 were sparse types and five were profuse types. All but one of the mutations were considered to cause truncation of the gene product by frame-shift due to deletion (14 cases) or nonsense mutation (seven cases). The location of the germ-line mutations seems to correlate with the two clinical types; germ-line mutations in five FAP patients with profuse polyps were observed between codon 1250 and codon 1464, whereas mutations in 17 FAP patients with fewer polyps were observed in the other regions of the APC gene. The result suggests that the number of colorectal polyps in FAP patients may be associated with a difference in the stability or biological function of the truncated APC protein.

Adenomatous Polyposis Coli↗
PubMed1996

APC gene mutations in human prostate cancer.

Prostate cancer is the most common cancer in aged men. Although ras and p53 gene mutations have been detected in some prostate cancers, the major genetic alterations involved in its carcinogenesis are not well understood. Mutation of the APC gene is responsible for colorectal tumors in which ras and p53 mutations are also often involved. Using PCR-SSCP analysis and sequencing, we examined 31 human primary prostate cancers (three cases at stage A, 10 at stage B, five at stage C and 13 at stage D) and four cases of lymph node metastasis from the stage D cases, for mutations in the APC gene. A mutation was detected in only one of the 35 samples (3%). This mutation, present in a primary stage B cancer, had a T to C transition in exon 15 at the first position of codon 956, resulting in substitution of histidine for tyrosine. This study clarified that APC gene mutations are not largely involved in the development of clinical prostate cancer.

Adult↗
PubMed1999

Germline mutations of the APC gene in Korean familial adenomatous polyposis patients.

We extensively analyzed genomic DNA and messenger RNA (mRNA) from 62 unrelated Korean patients with familial adenomatous polyposis (FAP) for identification of germline adenomatous polyposis coli (APC) gene mutations. We adopted both single-strand conformation polymorphism (SSCP) analysis and a method of analysis involving the reverse transcription-polymerase chain reaction (RT-PCR) followed by a protein truncation test (PTT). DNA sequencing confirmed all alterations represented by aberrant bands. Germline mutations were identified in 38 patients (61%). Nineteen of the detected mutations were presumed to be novel, thus emphasizing the heterogeneity of the mutational spectrum in Korean FAP patients. In the initial 48 patients, SSCP analysis was followed by PTT for those patients for whom no detectable mutations were found by SSCP. Using this combined approach, we identified germline APC gene mutations in 29 of the 48 FAP patients (60%), including 6 patients in whom SSCP analysis failed to distinguish the mutant allele. In the 14 later patients, we identified truncating mutations in 9 patients (64%) using PTT only. Our results confirm that the mutation detection rate with PTT was superior to that with SSCP, and suggest that PTT would be a more practical screening method to detect germline mutations of the APC gene in FAP patients.

Adenomatous Polyposis Coli↗
PubMed2001

Cytokine mRNA expression in mouse colon: IL-15 mRNA is overexpressed and is highly sensitive to a fibre-like dietary component (short-chain fructo-oligosaccharides) in an Apc gene manner.

On the basis of studies using the Min mouse model of colon carcinogenesis, we have recently proposed that a fibre-like food (short-chain fructo-oligosaccharides, sc-FOS) fermented in the colon may stimulate a mechanism of cancer immunosurveillance. In the present paper, we have investigated the expression of cytokines as potential effector molecules. Interleukin (IL-)4, IL-5, IL-13, IL-15 and interferon (INF)-gamma mRNAs were detected by a multi-probe ribonuclease protection assay in C57BL/6J and Min mouse colons. IL-15 mRNA expression was significantly amplified (P=0.01) by the sc-FOS-enriched diet in the colon of Min mice.

Animals↗