APC (Adenomatous Polyposis Coli) Tumor Suppressor☆
0
Citation
60
Reference
10
Related Paper
Keywords:
Adenomatous polyposis coli
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by the development of hundreds to thousands of colonic adenomas and an increased risk of colorectal cancer. Adenomatous polyposis coli (APC), encoding a large multidomain protein involved in antagonizing the Wnt signaling pathway, has been identified as the main causative gene responsible for FAP. In this study, we identified three novel mutations as well as two recurrent mutations in the APC in five Chinese FAP families by sequencing. Immunohistochemical analysis revealed that among these mutations, a nonsense mutation (c.2510C>G) and two small deletions (c.2016_2047del, c.3180_3184del) led to the truncation of the APC protein and the cytoplasmic and nuclear accumulation of β-catenin in the colorectal samples from affected individuals, respectively. Our study expands the database on mutations of APC and provides evidence to understand the function of APC in FAP.
Adenomatous polyposis coli
Nonsense mutation
Cite
Citations (12)
Adenomatous polyposis coli
Genetic linkage
Cite
Citations (31)
Desmoids tumors, characterized by monoclonal proliferation of myofibroblasts, could occur in 5-10% of patients with familial adenomatous polyposis (FAP) as an extra-colonic manifestation of the disease. FAP can develop when there is a germ-line mutation in the adenomatous polyposis coli gene. Although mild or attenuated FAP may follow mutations in 5΄ extreme of the gene, it is more likely that 3΄ extreme mutations haveamore severe manifestation of thedisease. A 28-year-old woman was admitted to the Cancer Institute of Iran with an abdominal painful mass. She had strong family history of FAP and underwent prophylactic total colectomy. Pre-operative CT scans revealed a large mass. Microscopic observation showed diffuse fibroblast cell infiltration of the adjacent tissue structures. Peripheral blood DNA extraction followed by adenomatous polyposis coli gene exon by exon sequencing was performed to investigate the mutation in adenomatous polyposis coli gene. Analysis of DNA sequencing demonstrated a mutation of 4 bpdeletions at codon 1309-1310 of the exon 16 of adenomatous polyposis coli gene sequence which was repeated in 3 members of the family. Some of them had desmoid tumor without classical FAP history. Even when there is no familial history of adenomatous polyposis, the adenomatous polyposis coli gene mutation should be investigated in cases of familial desmoids tumors for a suitable prevention. The 3΄ extreme of the adenomatous polyposis coli gene is still the best likely location in such families.
Adenomatous polyposis coli
Cite
Citations (0)
NAKAMURA, Y., NISHINO, I., KINZLER, K.W., VOGELSTEIN, B., MIYOSHI, Y., MIKI, Y., ANDO, H. and HORII, A. Mutations of the APC (Adenomatous Polyposis Coli) Gene in PAP (Familial Polyposis Coli) Patients and in Sporadic Colorectal Tumors. Tohoku J. Exp. Med., 1992, 168 (2), 141-147 - We have isolated several genes on chromosome 5q21 region tightly linked to hereditary familial polyposis coli (FAP) and Gardner's syndrome (GS). Two of these genes (MCC and APC) were found to be somatically altered by point mutation, deletion or insertion in tumors of sporadic colorectal cancer patients. One (APO) of them was also found mutations in the germ line of both APC and GS patients. The identification of these genes has significant implications for understanding the pathogenesis of colorectal neoplasia and for the diagnosis and counseling of individuals with inherited predispositions to colorectal cancer. - adenomatous polyposis coli (APC) gene; chromosome 5q21; familial polyposis coli (FAP); Gardner's syndrome (GS); mutation
Adenomatous polyposis coli
Gardner Syndrome
Cite
Citations (38)
Patients with familial adenomatous polyposis (FAP), which is caused by the dysfunction of the adenomatous polyposis coli (APC) protein, have the possibility of developing extracolonic manifestations, including thyroid cancer (TC), congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and gastric and duodenal adenomas. The pathogenesis of these disorders associated with FAP is considered to be affected by the site of the germline mutation on the APC gene as a genotype‑phenotype correlation. Moreover, β‑catenin binding sites consist of 20‑amino acid repeats (20‑AARs) in the APC protein, and they are essential for the development of colorectal adenomas and certain other extracolonic manifestations. The present study retrospectively analyzed the germline and somatic mutations of the APC gene in three papillary TC patients with FAP to analyze the association between the remaining number of 20‑AARs and the development of TC. The mutation sites of two TCs did not include 20‑AARs in each allele. In one patient, the remaining number of 20‑AARs was two in the germline mutation and zero in the somatic mutation. Together with the data on 13 FAP‑associated thyroid cancerous lesions in 3 FAP patients reported previously, the majority of the remaining numbers of 20‑AARs was zero in the TC patients with FAP (13/16; 81.3%). Consequently, the APC/β‑catenin signaling pathway may be strongly involved with the pathogenesis of TC with FAP. Further accumulation of FAP patients with TC will be required to confirm the molecular pathogenesis of TC.
Adenomatous polyposis coli
Pathogenesis
Cite
Citations (16)
Familial adenomatous polyposis (FAP) is an autosomal, dominantly inherited predisposition to colorectal cancer caused by germline mutations within the adenomatous polyposis coli (APC) gene, a key member of the Wnt signalling pathway. A new class of non-steroidal anti-inflammatory drugs (NSAIDs), the specific cyclooxygenase 2 (COX-2) inhibitors, have recently been applied for the treatment of FAP patients.The expressions of the Wnt members and targets APC, c-myc, cyclin D1 and COX-2, as measured by real-time quantitative RT-PCR, have been evaluated in fresh samples of normal colorectal mucosa and matched adenoma tissue of six unrelated FAP patients before and after treatment with meloxicam.A significant up-regulation of COX-2 in adenomas after treatment with meloxicam was found. Furthermore, in adenomas, a down-regulation of APC after treatment and a tight correlation of the expressions of the two Wnt targets, c-myc and cyclin D1, in both stages of treatment were observed.A feedback loop mediated by the peroxisome proliferator-activated receptor (PPAR) gamma is discussed as being responsible for the up-regulation of COX-2
Adenomatous polyposis coli
Meloxicam
Cite
Citations (24)
Development of one hundred or more adenomas in the colon and rectum is diagnostic for the dominantly inherited, autosomal disease Familial Adenomatous Polyposis (FAP). It is possible to identify a mutation in the Adenomatous Polyposis Coli (APC) gene in approximately 80% of the patients, and almost 1,000 different pathogenic mutations have been identified in the APC gene up till now. We report 12 novel and 24′ previously described germline APC mutations from 48 unrelated Danish families. Four families with the mutation localized in the 3′ region of the gene showed great variance in phenotypic presentation. © 2004 Wiley-Liss, Inc.
Adenomatous polyposis coli
Danish
Cite
Citations (12)
Familial adenomatous polyposis is characterized by the development of hundreds of adenomatous polyps located mainly in the colon and rectum. Patients with familial adenomatous polyposis who do not receive treatment will develop cancer before aged 40 years. This disease is caused by germline mutations in the adenomatous polyposis coli gene. Different studies have shown a correlation between the location of the mutation and the clinical phenotype, such as the grade of severity and/or the presence of extracolonic manifestations, such as desmoid tumors. This study was designed to identify germline mutation in the adenomatous polyposis coli gene in Chilean families with familial adenomatous polyposis.We examined the adenomatous polyposis coli gene in 24 Chilean families with familial adenomatous polyposis. The adenomatous polyposis coli gene was screened for mutations combining single strand conformation polymorphism technique, protein truncation test, and DNA sequencing.We detected 17 different truncating mutations in 21 of 24 families (87.5 percent); 9 of these were novel. Fourteen mutations were detected in exon 15, being the most frequent c.3,927_3,931delAAAGA, found in 3 of 21 families (14 percent). Eight families (33 percent) showed at least one patient affected with desmoid tumors, presenting mutations between codons 849 and 1,533. Interestingly, two mutations, c.3,632dupA and c.3,783_3,784delTT, leading into a truncating protein at codons 1,216 and 1,274, were associated with almost 100 percent penetrance for desmoid tumors among relatives.We achieved 87 percent mutation detection rate in adenomatous polyposis coli gene; more than 50 percent of them were novel. The high percentage of novel mutations found may be because of the genetic composition of the Chilean population, which is an admixture of Amerindian and Spaniards, and the scarce information in the literature about similar populations.
Adenomatous polyposis coli
Penetrance
Cite
Citations (13)
The adenomatous polyposis coli (APC) gene is important in the etiology of familial adenomatous polyposis(FAP). This study is to investigate the molecular mutation of the adenomatous polyposis coli gene, and indicate how it activates the anti-oncogenes to participate in cell apoptosis, thus leading to tumorigenesis. With the research into APC, it is significant to improve the hereditary predisposition and reduce the genetic load at the prenatal diagnosis.
Key words:
APC gene; FAP; Prenatal dignosis
Adenomatous polyposis coli
Etiology
Cite
Citations (0)
Germline mutations of the APC gene, which encodes a multidomain protein of 2843 amino acid residues, cause familial adenomatous polyposis (FAP). Three FAP clinical variants are correlated with the location of APC mutations: (1) classic FAP with profuse polyposis (>1000 adenomas), associated with mutations from codon 1250 to 1424; (2) attenuated FAP (<100 adenomas), associated with mutations at APC extremities (before codon 157 and after codon 1595); (3) classic FAP with intermediate colonic polyposis (100–1000 adenomas), associated with mutations located in the remaining part of APC . In an effort to decipher the clinical phenotype associated with APC C-terminal germline truncating mutations in patients with FAP, after screening APC mutations in one family whose members (n=4) developed gastric polyposis, colon oligo-polyposis and desmoid tumours, we performed a literature meta-analysis of clinically characterised patients (n=97) harbouring truncating mutations in APC C-terminus. The APC distal mutations identified in this study cluster with a phenotype characterised by colon oligo-polyposis, diffuse gastric polyposis and desmoid tumours. In conclusion, we describe a novel FAP clinical variant, which we propose to refer to as Gastric Polyposis and Desmoid FAP, that may require tailored management.
Adenomatous polyposis coli
Adenomatous polyps
Cite
Citations (15)