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PubMed1995

Screening South African familial adenomatous polyposis families for the five-nucleotide deletion at codon 1309 of the APC gene.

We report the occurrence of a common five-nucleotide deletion at codon 1309 of the adenomatous polyposis coli (APC) gene in four different South African population groups. The mutation causes familial adenomatous polyposis (FAP) in 18% (4/22 unrelated patients screened) of affected South Africans, which is similar to the frequency described in several other populations. Knowledge of the gene mutation underlying FAP enabled conclusive genetic testing of at-risk family members of four index patients in which this specific mutation has been characterized. The non-radioactive heteroduplex method described in this study allowed cost-effective molecular diagnosis directly after electrophoresis of enzymatically-amplified DNA in agarose gels. The resulting reduction of uncertainty for at-risk relatives is an important benefit of diagnosis at the DNA level.

Adenomatous Polyposis Coli↗

PubMed1999

The I1307K polymorphism of the APC gene in colorectal cancer.

BACKGROUND & AIMS: Colorectal cancer is one of the most frequent cancers in humans. Recently, a germline missense mutation, I1307K, was identified in the adenomatous polyposis coli (APC) gene that was suggested to increase cancer predisposition in Ashkenazi Jews. However, a second study indicated that the I1307K mutation did not contribute greatly to the risk of colon cancer in Ashkenazi breast-ovarian cancer families, and a role of mismatch repair deficiency was suggested. This study investigated the frequency of the I1307K mutation in several non-Ashkenazi Jewish populations. We also compared the distribution and frequency of APC mutations from colon tumors that were positive and negative for the I1307K mutation. Finally, the association between the presence of mutations in the I1307K region and mismatch repair deficiency was studied. METHODS: We tested for I1307K in 345 patients who were not Ashkenazi Jews using a heteroduplex screen. We also performed an extensive mutational analysis in this region of the APC gene on DNA extracted from 240 Italian, Finnish, and Hawaiian-Japanese colon tumors and determined replication error status. RESULTS: The I1307K mutation was not found among 345 non-Ashkenazis. Somatic mutations occurred at a lower frequency and were more randomly distributed when the I1307K allele was not present. The most common characteristic somatic mutation occurring around codon 1307 in I1307K-positive patients did not occur in tumors negative for the I1307K mutation. An association between mutations in the region around APC codon 1307 and mismatch repair deficiency was not found. CONCLUSIONS: Our findings support the hypothesis that the I1307K mutation is unique to the Ashkenazi Jews, contributes to tumor predisposition in colorectal cancer, and is unrelated to mismatch repair deficiency.

Adenomatous Polyposis Coli Protein↗

PubMedDate not supplied

Immunodetection of the presence or absence of full-length APC gene product in human colonic tissues.

In order to detect the presence or absence of wild-type adenomatous polyposis coli (APC) gene protein (APC) in human colonic tissues, we immunoaffinity purified two polyclonal rabbit antibodies (APC-1 and APC-2) directed against defined epitopes in the middle and carboxyl regions of APC. Such antibodies proved useful in western blot analysis of matched colonic mucosa and tumor sample pairs. A 300 kDa band corresponding to APC was detected in samples from normal colonic mucosa using both antibodies. No tumor samples (n = 14) showed a detectable 300 kDa band. SW480 colon carcinoma cells, known to express truncated APC lacking the carboxyl half of the protein, were also negative. These results indicate that our antibodies bind to full-length but not truncated APC. Thus, western blot analysis employing APC-1 and APC-2 antibodies may be used to evaluate the absence or presence of wild-type APC. The value of this methodology in detecting APC mutations, which mainly involve protein truncation or allelic loss, is based on its ability to demonstrate negative or reduced level of immunoreactivity toward full-length APC in tissues that contain such mutations.

Adenocarcinoma↗

PubMed1996

Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the APC gene. A clue for understanding the function of the APC protein.

The identification of germline mutations in a large number of clinically well-characterised patients with familial adenomatous polyposis (FAP) has allowed the unravelling of several genotype-phenotype relationships that can now be interpreted in the light of the structure and functional domains of the adenomatous polyposis coli (APC) protein. An attenuated phenotype has been found to be associated with mutations at the 5' end of the gene, while a severe clinical expression was found in patients with the most common mutation at codon 1309. So far, only few mutations in the 3' half of the gene have been published. We report on two families with a rather mild phenotype due to a frameshift mutation at codon 1597. These families may represent a clue for defining a 5' border for the occurrence of a second region of attenuated FAP that is localised in the 3' part of the APC gene. We propose a model to explain the relationship between the severity of the disease and the size of the mutant APC protein.

Adenomatous Polyposis Coli↗

PubMedDate not supplied

Evaluation of dHPLC in mutation screening of the APC gene in a Greek FAP cohort.

BACKGROUND: Germline mutations in the APC gene predispose to colorectal adenomas leading to cancer in over 80% of patients. A multitude of mutations, dispersed throughout the gene, have been described. We wanted to evaluate the usefulness of denaturing high performance liquid chromatography (dHPLC) for mutation screening. MATERIALS AND METHODS: Ten amplicons containing 14 mutations in the APC, previously identified by sequencing in 22 FAP patients, were analysed by dHPLC. dHPLC was also used to screen members of a family for a mutation identified in the proband. RESULTS: We analysed 10 amplicons under a total of 59 temperatures. Successful results were obtained from 51 out of 59 tested temperatures (86.4%). In all cases a different heteroduplex-homoduplex pattern was obtained from mutant DNA in at least two of the temperatures. All 14 mutations identified by sequencing were also detected using dHPLC. Sequence analysis of a large family confirmed the dHPLC results. CONCLUSION: Using dHPLC we detected all mutations previously identified by sequencing.

Adenomatous Polyposis Coli↗

PubMed1996

Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.

Desmoid tumors are slowly growing fibrous tumors highly resistant to therapy and often fatal. Here, we report hereditary desmoid disease (HDD), a novel autosomal dominant trait with 100% penetrance affecting a three-generation kindred. Desmoid tumors are usually a complication of familial adenomatous polyposis, a predisposition to the early development of premalignant adenomatous polyps in the colorectum due to chain-terminating mutations of the APC gene. In general, one or more members in approximately 10% of the FAP families manifest desmoid tumors. Affected individuals from the HDD kindred are characterized by multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Osteomas, epidermal cysts, and other congenital features were also observed. We show that HDD segregates with an unusual germ-line chain-terminating mutation at the 3' end of the APC gene (codon 1924) with somatic loss of the wild-type allele leading to tumor development.

Adolescent↗

PubMed2002

Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation.

BACKGROUND: Serrated adenoma is a precursor of colorectal cancer. AIM: To clarify possible genotype-phenotype correlations of serrated adenomas in familial adenomatous polyposis (FAP). PATIENTS: Eleven patients from eight families with FAP. METHODS: We performed total colonoscopy with multiple biopsies in patients. Neoplasia with a serrated glandular structure was regarded as a serrated adenoma. In each patient, germline mutations of the APC gene were determined. Colonic phenotype was compared with germline mutations of the APC gene. RESULTS: Serrated adenomas were found in three patients. These patients had macroscopic polyps <100 in number. Pedigrees with serrated adenomas had the truncating germline APC mutation at codon 161, 332, or 1556 while in the other pedigrees mutations were found between codons 554 and 1324. CONCLUSIONS: In FAP, serrated adenoma may be a phenotype characteristic of the attenuated form.

Adenoma↗

PubMed1997

Adrenocorticotropin-independent macronodular adrenocortical hyperplasia associated with multiple colon adenomas/carcinomas which showed a point mutation in the APC gene.

We report a male Japanese with corticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH) associated with multiple colon adenomas/carcinomas. The plasma cortisol level was elevated with no diurnal rhythm and was not suppressed with dexamethasone. Basal plasma ACTH was unmeasurable but subnormally increased after administration of metyrapone or corticotropin releasing hormone. Both adrenals were resected and weighed 90g; the histopathologic findings were similar to those of AIMAH as previously reported. At least 21 colon lesions which were adenomas or carcinomas, were resected endoscopically or surgically. This is the second reported case of the association of AIMAH with multiple colon polyps. An APC gene point mutation was detected in the colon cancer tissue by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP)/direct sequencing analysis at the putative splice acceptor site consensus sequence. However, no abnormality of APC gene was detected in the adrenocortical hyperplastic tissue. The possible etiological coexistence of these two diseases is discussed.

Adenoma↗

PubMed2004

Nuclear accumulation of beta-catenin without an additional somatic mutation in coding region of the APC gene in hepatoblastoma from a familial adenomatous polyposis patient.

The APC (adenomatous polyposis coli) gene status in a familial adenomatous polyposis (FAP) patient who developed hepatoblastoma was analyzed by the yeast color assay. Although a single base insertion at codon 462 resulting in truncation of its product was documented in hepatoblastoma cells, no additional somatic mutation was detectable in the whole coding sequence of the APC gene. The nuclear accumulation of beta-catenin without mutation in the exons 2-4 of the beta-catenin gene, however, was observed in the tumor cells by immunohistochemistry. The similar nuclear accumulation of beta-catenin without an additional somatic mutation in its gene, in the absence of somatic mutation in cluster region of the APC gene, has been previously reported in the single FAP case. Moreover, review in the hepatoblastoma cases in the FAP families showed a relatively later onset of the disease when compared with the sporadic cases. These observations suggest that accumulation of beta-catenin without an additional somatic mutation in the APC gene might be a possible mechanism for tumorigenesis of hepatoblastoma in the FAP families.

Adenomatous Polyposis Coli↗

PubMed2001

Somatic but not germline mutation of the APC gene in a case of cribriform-morular variant of papillary thyroid carcinoma.

We report a case of cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) in a 27-year-old woman. In addition to conventional cytologic features of typical PTC, the fine-needle aspirate showed numerous epithelial cells with abundant, eosinophilic, very elongated cytoplasm. Microscopically, the tumor was encapsulated and highly cellular and exhibited a mixture of cribriform, follicular, papillary, trabecular, solid, and spindle cell patterns of growth, with morular foci showing peculiar nuclear clearing (biotin-rich nuclei). The cells were cuboidal or tall, with frequent nuclear pseudostratification and abundant eosinophilic cytoplasm. The nuclei were usually hyperchromatic, with grooving, pallor, and pseudoinclusions. Angioinvasion and foci of capsular invasion were observed. Immunohistochemically, the neoplastic cells showed reactivity for thyroglobulin, epithelial membrane antigen, low- and high-molecular-weight cytokeratins, vimentin, neuron-specific enolase, CD15, estrogen and progesterone receptors, and bcl-2 protein. Molecular genetic analysis of the APC gene revealed a mutation in exon 15 at codon 1309 in tumoral tissue but not in peripheral lymphocytes. These findings support a relationship between the morphologic pattern of the C-MV of PTC and the APC gene and the existence of this variant as a sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma.

Adenocarcinoma↗

PubMed1996

APC gene: database of germline and somatic mutations in human tumors and cell lines.

A database is described in which over 700 mutations in the human APC gene of tumors (colon cancer predominantly) are compiled from the literature. It includes both molecular informations about the mutations and also clinical data about the patients. A software have been designed in order to analyse all these informations in the database.

Adenomatous Polyposis Coli↗

PubMed1996

The APC gene product and colorectal carcinogenesis.

The adenomatous polyposis coli (APC) gene has been found to be mutated during the development of sporadic colorectal tumours as well as in familial adenomatous polyposis patients (FAP), mutations being somatic or germinal respectively. The gene product is truncated in the carboxyterminal region but the role of the APC protein in tumorigenesis is not well understood. The purpose of this review is to reassess studies on the APC protein in an attempt to understand how the loss of its functions may cause or contribute to the development of carcinomas.

Adenomatous Polyposis Coli↗

PubMed1993

Somatic mutations of the APC gene in precancerous lesion of the stomach.

The adenomatous polyposis coli (APC) gene, responsible for familial adenomatous polyposis, is also associated with development of sporadic tumors in digestive system as colon, stomach, or pancreas. In order to investigate whether or not APC mutations occur as an early genetic event during gastric carcinogenesis, we examined somatic mutations of APC in flat adenomas of the stomach. DNAs isolated from flat adenomas were examined by means of an RNase protection analysis coupled with polymerase chain reaction (PCR) followed by DNA sequencing of the PCR products. By screening a mutation cluster region (MCR: codons between 1286 and 1513) of APC in which two-thirds of somatic mutations were detected in colorectal tumors, somatic mutations were found in four of ten flat adenomas: three of which caused truncation of the gene product due to a nonsense mutation or 4-bp deletion; one other was a point mutation that altered amino acid from alanine to threonine. Our results imply that APC plays a crucial role in an early step of gastric carcinogenesis, as was observed in colorectal carcinogenesis.

Adenoma↗

PubMed1999

Loss of heterozygosity and protein expression of APC gene in renal cell carcinomas.

This study evaluated the potential contribution of the APC gene to malignant transformation in patients with renal cell carcinoma. We tested 36 human renal cell carcinoma samples and 18 adjacent normal kidney tissues for the expression of APC protein, both wild and truncated types, by western blot using antibodies that recognize either the carboxy or the amino epitope of the APC protein. The same tumor samples together with autologous peripheral blood were also analyzed at the DNA level. Using specific oligonucleotide primers for exons 11 and 15, gene instability was followed by polymerase chain reaction/loss of heterozygosity (LOH) (on the basis of restriction fragment length polymorphism). Molecular data were also compared to pathohistological diagnosis, TNM stage, and patient's age using multivariate statistical methods. All normal renal tissues revealed expression of the wild-type APC protein. Neither wild nor mutant type proteins were found in 36% (13/36) of tumor samples; the rest of tumor tissues expressed the wild-type protein (312 kDa). Mutated APC protein, with a molecular weight of 117 kDa, was found in only one tumor sample. From 36 tumor samples 16 (44.4%) were informative for RsaI exon 11 polymorphic site, while only half of these (8/16) demonstrated LOH. From 13 tumor samples that had no detectable protein product by western blot analysis eight were homozygous for the exon 11 polymorphism and were tested for another polymorphic site, MspI/exon 15. The overall proportion of LOH cases for both polymorphisms tested was 52.9% (9/17). Pathohistological diagnosis and molecular data showed no correlation. However, multivariate analysis determined a stage strong positive correlation of age and TNM with the presence of LOH and the absence of the wild-type APC protein. Out results suggest that the APC tumor suppressor gene plays a role in renal carcinogenesis. Alterations in this gene are responsible for tumor evolution and progression, but cannot be considered as a first event in tumor initiation.

Adenomatous Polyposis Coli Protein↗

PubMed1998

APC gene: database of germline and somatic mutations in human tumors and cell lines.

A database (http://perso.curie.fr/tsoussi ) is described, in which over 1000 mutations in the human APC gene of tumors (colon cancer predominantly) are compiled from the literature. It includes both molecular information about the mutations and clinical data about the patients. Software has been designed to analyse all this information in the database.

Adenomatous Polyposis Coli↗

PubMed2005

Cytoplasmic expression of E-cadherin and beta-Catenin correlated with LOH and hypermethylation of the APC gene in oral squamous cell carcinomas.

BACKGROUND: Inactivation of the adenomatous polyposis coli (APC) gene results in accumulation and translocation of beta-Catenin, which are important for malignant development. The aim of the present study is to investigate the possible role of APC/beta-Catenin pathway in oral squamous cell carcinomas. METHODS: The DNA from 34 patients was examined for loss of heterozygosity (LOH) at two markers surrounding the APC, and for hypermethylation of the APC promoter by using methylation-specific polymerase chain reaction (MS-PCR). Fifteen of 34 samples were stained immunohistochemically to show the expression of E-cadherin and beta-Catenin. RESULTS: We found that cytoplasmic rather than membrane staining of E-cadherin and beta-Catenin was a prominent aberrant tumour-related alteration, and that this expression was mainly present in moderately and poorly differentiated tumours. LOH and hypermethylation of the APC promoter was found in four of 31 and five of 34 carcinoma samples, respectively. Four of five cases presenting LOH/hypermethylation showed cytoplasmic expression of E-cadherin and beta-Catenin by immunohistochemical (IHC) staining. CONCLUSION: The present results indicate that LOH at the APC locus or hypermethylation of the APC promoter 1a may lead to free beta-Catenin accumulation in cytoplasm of oral carcinoma cells and thereby to oral malignant progression.

Cadherins↗

PubMed2004

Chromosomal instability and APC gene mutations in human sporadic colorectal adenomas.

The mechanisms by which adenomatous polyposis coli (APC) gene mutations contribute to colorectal tumourigenesis and progression are still not fully understood. Using in vitro mouse embryonic stem cells, APC mutations have been proposed to dysregulate the interactions between kinetochores and microtubules during mitosis, leading to chromosomal instability (CIN) and aneuploidy. A link between APC mutations and aneuploidy in vivo among human sporadic colorectal adenomas has not been reported previously and was therefore investigated in the present series of 61 adenomas. Multi-parameter flow cytometry, based on scattering and fluorescence from the DNA-specific 4,6-diamidino-2-phenylindole-2-hydrochloride (DAPI) dye, which separates epithelial from stromal lymphocyte nuclei, was used to evaluate the DNA index (DI) and to sort epithelial nuclei. Additionally, DNA extracted from these sorted nuclei was used to analyse APC mutations by DNA sequencing. Aneuploidy was present in 20 of 61 adenomas (33%), with 15 of these 20 cases (75%) having a near-diploid DI (DI different from 1 and less than 1.3). APC mutations were detected in 19 adenomas (31%): 12 were within or downstream of the mutation cluster region (MCR), roughly defined by codons 1200-1500, and seven were upstream of the MCR. Overall, the prevalence of aneuploidy in APC wild-type and mutated adenomas was 26% and 47%, respectively, and no statistically significant association was found between APC status and DI (p = 0.142). However, when APC mutations were subdivided into two groups, ie occurring within/downstream of the MCR and upstream of the MCR, the association of APC mutations within and downstream of the MCR with aneuploidy was statistically significant (p = 0.017). In conclusion, the present data suggest that the type of APC mutation may play a role in the origin of CIN in vivo in human sporadic colorectal adenomas and that APC mutations within and downstream of the MCR, and large-scale chromosomal alterations, may co-operate in the progression of a subgroup of adenomas.

Adenoma↗

PubMed1998

The APC gene I1307K variant is rare in Norwegian patients with familial and sporadic colorectal or breast cancer.

Recently, a T-to-A transversion creating an 8-base mononucleotide tract in the APC gene, resulting in substitution of lysine for isoleucine at codon 1307 (I1307K), was found in a subset of Ashkenazi Jews. This sequence variant was most frequent in colorectal cancer patients with a positive family history of colorectal cancer. To determine whether the I1307K variant plays a role in colorectal or breast cancer predisposition in the Norwegian population, we have analyzed blood samples from 210 colorectal cancer patients and 183 breast cancer patients by PCR and direct sequencing. Thirty-seven of the colorectal cancer patients had a positive family history of cancer. Among the breast cancer patients, 24 had a family history of colorectal cancer and 75 a family history of breast and/or ovarian cancer. Only one colorectal cancer patient who belonged to a Jewish family was found to carry the A variant. Our data show that the I1307K variant is rare in the Norwegian population and should not be viewed as a candidate for susceptibility testing for colorectal cancer.

Alleles↗