National Cancer Institute®
Last Modified: September 1, 2002
UI - 11876475
AU - Powell SM
TI - Direct analysis for familial adenomatous polyposis mutations.
SO - Mol Biotechnol 2002 Feb;20(2):197-207
AD - Division of Gastroenterology, University of Virginia Health System, Charlottesville 22908, USA. email@example.com
The spectrum of disease causing mutations is immense. It just so happens that the overwhelming majority of genetic alterations in the APC gene with leads to adenomatous polyposis coli generate truncated gene products. This observation lead to the development of the in vitro synthesis protein assay (protein truncation test) which is a sensitive method to detect these truncated gene products from patient samples. This article describes the assay to detect truncated proteins for the APC gene, which can also be applied to other disease causing genetic alterations which commonly lead to truncations such in HNPCC, von Hippel-Lindau, osteogenesis imperfecta, retinoblastoma, BCRAI, beta-thalassemia, hemophilia B, Duchenene and Becker muscular dystrophy.
UI - 10710046
AU - McGarrity TJ; Kulin HE; Zaino RJ
TI - Peutz-Jeghers syndrome.
SO - Am J Gastroenterol 2000 Mar;95(3):596-604
AD - Department of Medicine, The Milton S. Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey 17033-0850, USA.
Peutz-Jeghers syndrome (PJS) is an unusual polyposis syndrome that has enjoyed a rich and somewhat confusing history. Mucocutaneous pigmentation and diffuse gastrointestinal hamartomas are the hallmark features of this autosomal dominant inherited condition. Peutz-Jeghers syndrome is now also recognized as a cancer predisposition syndrome. In this review, we highlight the historical aspects of PJS polyposis with special emphasis on its extraintestinal manifestations, particularly genital tract tumors. A PJS management scheme for clinicians is included.
UI - 11917214
AU - Piard F; Chapusot C; Ecarnot-Laubriet A; Ponnelle T; Martin L
TI - Molecular markers of heterogeneity in colorectal cancers and adenomas.
SO - Eur J Cancer Prev 2002 Feb;11(1):85-97
AD - Service d'Anatomopathologie, Faculte de Medecine BP 87900, F-21079 Dijon, France. firstname.lastname@example.org
UI - 11932472
AU - Giardiello FM; Yang VW; Hylind LM; Krush AJ; Petersen GM; Trimbath JD;
TI - Piantadosi S; Garrett E; Geiman DE; Hubbard W; Offerhaus GJ; Hamilton SR Primary chemoprevention of familial adenomatous polyposis with sulindac.
SO - N Engl J Med 2002 Apr 4;346(14):1054-9
AD - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
BACKGROUND: Familial adenomatous polyposis is caused by a germ-line mutation in the adenomatous polyposis coli gene and is characterized by the development of hundreds of colorectal adenomas and, eventually, colorectal cancer. Nonsteroidal antiinflammatory drugs can cause regression of adenomas, but whether they can prevent adenomas is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled study of 41 young subjects (age range, 8 to 25 years) who were genotypically affected with familial adenomatous polyposis but phenotypically unaffected. The subjects received either 75 or 150 mg of sulindac orally twice a day or identical-appearing placebo tablets for 48 months. The number and size of new adenomas and side effects of therapy were evaluated every four months for four years, and the levels of five major prostaglandins were serially measured in biopsy specimens of normal-appearing colorectal mucosa. RESULTS: After four years of treatment, the average rate of compliance exceeded 76 percent in the sulindac group, and mucosal prostaglandin levels were lower in this group than in the placebo group. During the course of the study, adenomas developed in 9 of 21 subjects (43 percent) in the sulindac group and 11 of 20 subjects in the placebo group (55 percent) (P=0.54). There were no significant differences in the mean number (P=0.69) or size (P=0.17) of polyps between the groups. Sulindac did not slow the development of adenomas, according to an evaluation involving linear longitudinal methods. CONCLUSIONS: Standard doses of sulindac did not prevent the development of adenomas in subjects with familial adenomatous polyposis.
UI - 12136240
AU - Su LK; Kohlmann W; Ward PA; Lynch PM
TI - Different familial adenomatous polyposis phenotypes resulting from deletions of the entire APC exon 15.
SO - Hum Genet 2002 Jul;111(1):88-95
AD - Department of Molecular and Cellular Oncology, Box 79, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston 77030, USA. email@example.com
Germline mutations of the adenomatous polyposis coli ( APC) gene cause familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease that predisposes patients to colorectal cancer. The APC gene is composed of 15 coding exons and encodes an open reading frame of 8.5 kb. The 3' 6.5 kb of the APCopen reading frame is encoded by a single exon, exon 15. Most identified APC mutations are at the 5' half of the APC open reading frame and are nucleotide substitutions and small deletions or insertions that result in truncation of the APC protein. Very few well-characterized gross alterations of APC have been reported. Patients with FAP typically develop hundreds to thousands of colorectal tumors beginning in their adolescence. A subgroup of patients with FAP who develop fewer tumors at an older age have what is called attenuated FAP (AFAP). Accumulating evidence indicates that patients carrying germline APC mutations in the first four coding exons, in the alternatively spliced region of exon 9, or in the 3' half of the coding region usually develop AFAP. We characterized two germline APC alterations that deleted the entire APC exon 15 as the result of 56-kb and 73-kb deletions at the APC locus. A surprising finding was that one proband had the typical FAP phenotype, whereas the other had a phenotype consistent with that of AFAP.
UI - 12174906
AU - Dobbie Z; Muller PY; Heinimann K; Albrecht C; D'Orazio D; Bendik I;
TI - Muller H; Bauerfeind P Expression of COX-2 and Wnt pathway genes in adenomas of familial adenomatous polyposis patients treated with meloxicam.
SO - Anticancer Res 2002 Jul-Aug;22(4):2215-20
AD - Division of Medical Genetics, University Clinics, Basel, Switzerland.
BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: A feedback loop mediated by the peroxisome proliferator-activated receptor (PPAR) gamma is discussed as being responsible for the up-regulation of COX-2
UI - 12135043
AU - Cao Y; Pieretti M; Marshall J; Khattar NH; Chen B; Kam-Morgan L; Lynch H
TI - Challenge in the differentiation between attenuated familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer: case report with review of the literature.
SO - Am J Gastroenterol 2002 Jul;97(7):1822-7
AD - Department of Internal Medicine, St Luke's Hospital, Chesterfield, Missouri 63017, USA.
The clinical differentiation between hereditary nonpolyposis colorectal cancer (HNPCC) and attenuated familial adenomatous polyposis (AFAP) is very difficult. The 62-yr-old proband presented with duodenal adenocarcinoma. His history of subtotal colectomy for colon cancer, the rarity of duodenal adenocarcinoma in the general population, and his family history of colon cancer made us suspect that he might have FAP. We investigated this family by obtaining medical records and performing gene analysis. The proband had only 10 adenomatous colon polyps when he underwent subtotal colectomy for the cancer, so classic FAP was excluded. His family history included rectal cancer in his brother at 69 yr of age, colon cancer in his mother at 75 yr, and colon cancer in one maternal cousin at 42 yr. Three months after we started to study this family, the proband's 32-yr-old son presented with rectal cancer. His family fulfilled the Amsterdam criteria for HNPCC, but AFAP could not be excluded. Upon gene testing, the proband was negative for APC gene germline mutation, which made AFAP highly unlikely. Moreover, high microsatellite instability (MSI) was detected in his adenomas and cancer tissues. The fulfillment of Amsterdam criteria, the exclusion of FAP and AFAP, and the high MSI established the diagnosis of HNPCC in this family. We also summarize the differences between FAP, AFAP, and HNPCC; extend the graphic description of the MSI mechanism; and propose a diagnostic strategy for HNPCC.
UI - 11950865
AU - Albuquerque C; Cravo M; Cruz C; Lage P; Chaves P; Fidalgo P; Suspiro A;
TI - Nobre Leitao C Genetic characterisation of patients with multiple colonic polyps.
SO - J Med Genet 2002 Apr;39(4):297-302
UI - 11983341
AU - Bonk T; Humeny A; Sutter C; Gebert J; von Knebel Doeberitz M; Becker CM
TI - Molecular diagnosis of familial adenomatous polyposis (FAP): genotyping of adenomatous polyposis coli (APC) alleles by MALDI-TOF mass spectrometry.
SO - Clin Biochem 2002 Mar;35(2):87-92
AD - Institut fur Biochemie, Emil-Fischer-Zentrum, Universitat Erlangen-Nurnberg, Fahrstrasse 17 D-91054, Erlangen, Germany.
OBJECTIVES: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposition syndrome caused by germ line mutations in the adenomatous polyposis coli gene (APC). For prophylactic colectomy, timely identification of patients at risk is urgent. Here, matrix assisted laser desorption ionization - time of flight - mass spectrometry (MALDI-TOF-MS) genotyping is offered for an efficient molecular diagnosis of APC germline mutations. DESIGN AND METHODS: The four most frequent APC germ line mutations (three deletions, one point mutation) were genotyped by allele specific elongation and termination of extension primers. The extension products generated were analyzed by MALDI-TOF-MS. RESULTS: Following PCR amplification and allele specific primer extension reactions MALDI-TOF-MS allowed the unambiguous identification of informative nucleic acid fragments corresponding to distinct genotypes or mutants even in duplex assays. Results were confirmed by DNA-sequencing. CONCLUSIONS: Due to its high molecular resolution and accuracy, this method is highly suitable as an alternative for clinical APC genotyping.
UI - 12171945
AU - Wright NA; Poulsom R
TI - Top down or bottom up? Competing management structures in the morphogenesis of colorectal neoplasms.
SO - Gut 2002 Sep;51(3):306-8
AD - Histopathology Unit, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. firstname.lastname@example.org
UI - 12171967
AU - Crabtree MD; Tomlinson IP; Hodgson SV; Neale K; Phillips RK; Houlston RS
TI - Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.
SO - Gut 2002 Sep;51(3):420-3
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. email@example.com
BACKGROUND: Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between APC genotype and phenotype but there remains significant intrafamilial variation. In the Min mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes. AIMS: To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of modifier genes. METHOD: We systematically examined polyp numbers in colectomy specimens from patients with classical FAP. Variation both between and within families was analysed. Formal modelling of the segregation of disease severity in families was performed RESULTS: There was strong evidence for a relationship between site of mutation and the number of colorectal polyps, with germline mutations in the "cluster region" causing the most severe disease and those with mutations between codons 1020 and 1169 having the mildest disease. In addition to this genotype-phenotype relationship, we found evidence for non-APC linked genetic modifiers of disease expression. First degree relatives had more similar polyp counts than more distant relatives. Formal modelling of the segregation of disease severity in families revealed further evidence for the action of modifier genes, with a best fit to a mixed model of inheritance. CONCLUSION: Our data provide good evidence to support the hypothesis that modifier genes influence the severity of FAP in humans.
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