Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(1) Familial adenomatous polyposis is a genetic disorder associated with multiple adenomatous colorectal polyps that invariably progress to colorectal cancer. Gastroduodenal polyposis and extra-gastrointestinal desmoid tumours are other major sources of morbidity in these patients. (2) The current strategy used to prevent colorectal cancer in patients with APC gene mutations consists of yearly monitoring starting in adolescence, and prophylactic colectomy in early adulthood if polyposis occurs. (3) On the basis of pathophysiological, experimental and epidemiological evidence, some specialists have postulated that certain nonsteroidal antiinflammatory drugs (NSAIDs) might have a preventive effect on colorectal adenomas and cancer. (4) Aspirin and sulindac were tested for the prevention of polyps in patients with familial adenomatous polyposis, with uncertain results and weak evidence of effectiveness. (5) Celecoxib was tested in a comparative randomised double-blind trial lasting 6 months. It involved 77 patients with familial polyposis and colorectal polyps, and 6 patients with only duodenal polyps. On the basis of composite endoscopic criteria, a celecoxib dose of 800 mg/day (but not 200 mg/day) reduced the number and surface area of adenomatous colorectal polyps in patients with familial adenomatous polyposis. It is not known whether celecoxib also reduced the risk of colorectal cancer. A global qualitative analysis suggested that celecoxib was also effective in reducing duodenal polyps. (6) Nearly one-third of patients receiving celecoxib 800 mg/day in this trial developed rectal bleeding. Another preventive trial was stopped when an excess of cardiovascular events was found in patients taking celecoxib. (7) The long-term risk-benefit balance of celecoxib 800 mg/day is not known nor whether efficacy persists after treatment discontinuation. (8) In practice, it is better not to use celecoxib to prevent colorectal cancer: its efficacy has not been demonstrated, even in familial polyposis, and it carries a major risk of bleeding and cardiovascular events.
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PMID:Celecoxib: new indication. Colorectal cancer: no preventive benefit. 1654 99

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (less than ten) was not typical of polyposis; therefore, the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumor tissue showed high-grade instability, and a subsequent, immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumor cells. Prophylactic colectomy was performed, and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as a frameshift mutation in exon 7 (c.1191_1192dupG). Both parents of the proband were analysed for MSH2 and APC mutations, and in the father, a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At the follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumor.
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PMID:Double frameshift mutations in APC and MSH2 in the same individual. 1583 12

Familial adenomatous polyposis (FAP) is an inherited condition causing numerous adenomatous colorectal polyps and a markedly elevated risk of colon cancer. FAP may be associated with various extracolonic manifestations such as desmoid fibromatosis and osteomas (termed Gardner's syndrome) and brain tumors, usually medulloblastoma or glioma [termed Brain Tumor Polyposis (BTP) syndrome type 2]. We describe a pediatric patient who initially presented with prolactinoma and later was found to have Gardner's syndrome. A germline mutation of the APC (adenomatous polyposis coli) gene was identified. Our case illustrates the association between prolactinoma and FAP, which may represent a rare subtype of Gardner's and BTP syndromes.
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PMID:Prolactinoma as the first manifestation of Gardner's syndrome. 1686 50

Familial adenomatous polyposis (FAP) is an autosomal dominant condition mostly due to a mutation of the APC gene on the chromosome 5q. Carriers have an almost 100% chance of developing colorectal cancer after having multiple (typically 100s to 1000s) of adenomatous polyps. It is usually readily identified through this phenotype of multiple adenomas. Correlations between the location of the family-specific mutation on the APC gene and clinical manifestations of the disease are of some assistance in clinical management, though there is heterogeneity in clinical course even between family members with the same mutation. FAP is important to recognize, as there are disease-specific management implications with respect to offering mutational analysis of the APC (and perhaps other) genes for predictive testing of other family members, endoscopic diagnostic procedures, surveillance planning, and surgical management. Extra-colonic manifestations, including duodenal polyposis, desmoid disease and other tumours, can dominate clinical care after colectomy. The inheritable and lethal nature of the disease, together with the availability of effective treatment strategies, makes a sensitive clinical and psychosocial approach important to maximize compliance and good outcomes for all members of affected families.
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PMID:Familial adenomatous polyposis: The practical applications of clinical and molecular screening. 1699 68

Desmoid tumours are rare neoplasms of fibroblastic origin which arise with disproportionate frequency in patients with familial adenomatous polyposis (FAP). They are thought to develop in about 10-25% of FAP patients and may be the leading cause of death amongst those who have undergone colectomy. Risk factors include trauma, having a distal germline APC mutation, having a family history of desmoids, and probably oestrogens. In very high-risk individuals there may be a case for delay of colectomy or chemoprophylaxis at the time of surgery. Desmoids are now known to be true neoplasms but with normal telomere length and telomerase activity. FAP-associated tumours seem to carry biallelic APC mutations, one of which lies in the distal part of the gene. Such loss of wild-type APC seems to occur relatively late in tumour development. It is likely that beta-catenin plays an important role in tumourigenesis. FAP-associated desmoids tend to arise in the abdomen or abdominal wall. CT scanning gives the best information on tumour anatomy whilst T2-weighted MRI indicates likely behaviour. Treatment may simply consist of observation. Otherwise, usual first-line therapy is with sulindac with or without an anti-oestrogen. Cytotoxic chemotherapy is an option in unresectable tumours. Surgery is a reasonable first-line treatment in abdominal wall tumours but is risky for intra-abdominal tumours and may necessitate massive small bowel resection. Desmoids are the greatest remaining challenge in the management of FAP and further research into their aetiology needs to be combined with multicentre clinical trials of new treatments in order to improve management of the disease.
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PMID:Current ideas in desmoid tumours. 1699 73

Analysis of APC mutations in colonic and duodenal tumours from familial adenomatous polyposis (FAP) patients has shown that the site of the first hit, the germline mutation, can predict the type and position of the somatic mutation or 'second hit'. The two APC mutations are selected on the basis of a 'just right' level of beta-catenin signalling in intestinal tumours achieved through retention of some of the seven 20-amino-acid beta-catenin degradation repeats. Desmoids are a life threatening extra-colonic manifestation in FAP patients. These aggressive tumours of mesenchymal origin are, at present, poorly characterized in terms of mutational APC spectra. We have investigated somatic mutations in the largest cohort of FAP-associated desmoids to date, and combined our results with previously published data. Somatic mutations were found to occur non-randomly and the position of the germline mutation shown to be a major determinant of the somatic mutation, a characteristic shared with intestinal tumours from FAP patients. In contrast to colonic polyps, loss of heterozygosity in desmoids involved deletion rather than mitotic recombination. While tumours from the colorectum and upper gastrointestinal tract usually retain one to two and three to four beta-catenin degradation repeats, respectively, most desmoids preferentially retain two repeats (P < 0.001, chi2 test). In addition, most desmoids with two APC hits (87%, 26/30) had one mutated allele with no 20-amino acid repeats (P < 0.001). This feature, unique among FAP tumours, indicates that a mutation deleting all repeats from one allele may be an important component in maintaining appropriate levels of beta-catenin signalling levels in desmoid tumour cells.
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PMID:APC mutations in FAP-associated desmoid tumours are non-random but not 'just right'. 1713 76

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care-common for other disorders-is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase. We present a clinical overview of extra-intestinal manifestations, including management and treatment options for the FAP syndrome. Furthermore, we provide recommendations for surveillance of FAP complications based on available literature.
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PMID:Extra-intestinal manifestations of familial adenomatous polyposis. 1926 42

A 25-year-old female with familial adenomatous polyposis (FAP) presented with an abdominal tumor just below the scar due to a colectomy performed 15 months previously. This tumor (tumor A) measured 7 cm in diameter, was diagnosed as a desmoid tumor of the abdominal wall, and was excised. Despite the subsequent administration of sulindac (300 mg daily for 1 year), a desmoid tumor recurred at the same site. Excision was performed again when the tumor was 8 cm in diameter, and examination revealed it to consist of a large tumor (B) and a small tumor (C) that bulged out from tumor B. Germ-line APC analysis showed a C deletion at codon 1460 resulting in a stop codon. Two somatic mutations were observed in tumor A: a TCAA deletion at codon 1068 and a deletion of a codon at bp 1192-2097. In tumor B, a somatic mutation was found at codon 1041 changing CAA to TAA. We could not detect any somatic mutations in tumor C. We conclude that somatic mutation analysis of the APC gene can be used to identify whether a recurrent desmoid tumor in a patient with FAP is a new primary tumor or a recurrence from microscopic remnants of the original tumor.
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PMID:Identification of somatic APC mutations in recurrent desmoid tumors in a patient with familial adenomatous polyposis to determine actual recurrence of the original tumor or de novo occurrence. 1870 58

Desmoid tumors (desmoid-type fibromatoses) are locally aggressive soft tissue tumors associated with the Wnt/beta-catenin signaling pathway (APC-beta-catenin-Tcf pathway). Matrix metalloproteinase-7, which is one of the target genes of the Wnt/beta-catenin signaling pathway, has been reported to play an important role in tumor progression. We examined the immunohistochemical expression of beta-catenin and matrix metalloproteinase-7 in 72 samples (63 primary and 9 recurrent samples, 63 patients) of sporadic desmoid tumors without familial adenomatous polyposis, and the genetic alteration of the beta-catenin gene in 33 frozen materials (22 primary and 11 recurrent samples, 22 patients). We further examined messenger RNA expression of matrix metalloproteinase 7 by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and compared the results with those of normal skeletal muscles. Immunohistochemically, there was a statistically significant correlation between widespread nuclear expression of beta-catenin and overexpression of matrix metalloproteinase-7 (P < .01 in extra-abdominal desmoid, Fisher test). There were 7 missense point mutations in the 22 primary frozen samples (32%). In the beta-catenin mutated group, matrix metalloproteinase-7 messenger RNA expression was significantly higher than that of the beta-catenin wild-type group (P = .0018, Mann-Whitney U test). Our results suggest that the matrix metalloproteinase-7 gene may be up-regulated by mutated or continuously elevated beta-catenin protein and that the matrix metalloproteinase-7 gene may also be targeted in the Wnt/beta-catenin signaling pathway in sporadic desmoid tumors.
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PMID:Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. 1871 18

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.
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PMID:The pleiotropic phenotype of Apc mutations in the mouse: allele specificity and effects of the genetic background. 1872 78


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