Molecular Diagnosis of Familial Adenomatous Polyposis

Johns Hopkins University, Baltimore, Maryland, United States
New England Journal of Medicine (Impact Factor: 55.87). 01/1994; 329(27):1982-7. DOI: 10.1056/NEJM199312303292702
Source: PubMed


Familial adenomatous polyposis is an inherited disease characterized by multiple colorectal tumors. The diagnosis has classically been based on the detection of multiple colorectal adenomas. The recent identification of germline mutations of the APC gene in patients with familial adenomatous polyposis makes presymptomatic molecular diagnosis possible, but the widespread distribution of the many mutations within this very large gene have heretofore made the search for such mutations impractical. We describe a novel approach that allows molecular genetic diagnosis in the majority of patients with the disease.
We screened 62 unrelated patients from the Johns Hopkins Familial Adenomatous Polyposis Registry for germline APC mutations. Primary screening was accomplished by analysis of protein synthesized in vitro from surrogate APC genes. In addition, the relative amount of transcript from each APC allele was determined with an allele-specific--expression assay.
The protein assay revealed truncated protein in 51 of the 62 patients (82 percent). In 3 of the 11 remaining patients, the allele-specific--expression assay revealed significantly reduced expression of one allele of the APC gene. The use of these two assays in combination successfully identified germline APC mutations in 87 percent of the 62 patients.
The protein and allele-specific--expression assays provide a practical and sensitive method for molecular diagnosis of familial adenomatous polyposis. This approach will facilitate care, allowing routine testing of subjects at risk and genetic confirmation of spontaneous mutations.

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    • "Familial adenomatous polyposis (FAP) is an inherited human disease characterized by numerous colorectal tumorigenesis (Kinzler and Vogelstein, 1996). FAP is caused by mutation in the adenomatous polyposis coli (APC) tumor suppressor gene (Powell et al., 1993). Min (multiple intestinal neoplasia) mouse is a murine model of human FAP (Moser et al., 1990), which has nonsense mutation at codon 850 in Apc gene (Su et al., 1992). "
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    ABSTRACT: Inflammation is potential risk factor of various human malignancies. Inflammatory bowel syndromes such as ulcerative colitis are well known as risk factors for colon cancer. Here, we examined enhancing effects of dextran sulfate sodium (DSS)-associated inflammation on X-irradiation induced colonic tumorigenesis in Min and wild-type (WT) mice. Animals were X-irradiated at 1.5 Gy at 5 weeks of age (at 0 experimental week) and 2% DSS in drinking water was administered at 5 or 11 experimental weeks. Mice were sacrificed at 16 weeks and incidence and multiplicity of colonic tumors were assessed. Incidence of colonic tumors in Min mouse was increased from 33.3% to 100% (p<0.05) with X-irradiation alone, whereas no tumors were developed in WT mice. In DSS-treated Min mice, X-irradiation increased the number of colonic tumors. Total number of colonic tumors was increased 1.57 times to 30.7±3.83 tumors/mouse with X-irradiation+DSS at 5 weeks comapared to 19.6±2.9 in corresponding DSS alone group (p<0.05). When the duration of inflammation was compared, longer period of DSS effect promoted more colonic tumorigenesis. Collectively, we conclude that X-irradiation and DSS-induced inflammation act synergistically for colonic tumorigenesis.
    Asian Pacific journal of cancer prevention: APJCP 07/2013; 14(7):4135-9. DOI:10.7314/APJCP.2013.14.7.4135 · 2.51 Impact Factor
    • "Inflammatory bowel disease (IBD) represents an example of a condition that greatly increases the risk of colorectal cancer.[1] Furthermore, the development of CRC is influenced by a genetic predisposition, which is especially high for somatic mutations of the tumor suppressor gene adenomatosis polyposis coli (APC) that causes familial adenomatosis coli syndrome.[2] "
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    ABSTRACT: Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci-adenoma-carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS-treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.
    Journal of Carcinogenesis 03/2011; 10(1):9. DOI:10.4103/1477-3163.78279
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    • "The Adenomatous polyposis coli gene (APC) is found on the long arm of chromosome 5 locus 21.13 The APC gene can be detected by Protein truncation test.14 Genetic testing of first degree relatives will help identify the APC gene carriers while allaying the anxiety of non carriers. "
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    ABSTRACT: Familial adenomatous polyposis is rare. Three cases were previously reported in Nigeria. An intriguing feature of this case is an ulcerated jejunal carcinoma which was metastatic rather than synchronous carcinoma. This patient presented with partial large bowel obstruction and the pathological analysis revealed 4 invasive adenocarcinomas, 3 in the colon and 1 in the jejunum (Dukes stage D). Palliative pancolectomy and jejunal tumour resection with chemotherapy was offered to him. He died eight months after surgery from disease progression. The challenges of managing a hereditary cancer syndrome in a resource poor country are highlighted.
    Rare tumors 10/2010; 2(4):e66. DOI:10.4081/rt.2010.e66
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