• Genetic and clinical characterisation of familial adenomatous polyposis: a population based study.

• [Genetic analysis in familial adenomatous polyposis]

• Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal

• Cancer genetics and their application to individualised medicine.

• When is molecular genetic testing for colorectal cancer indicated?

• Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc

• [Polyps (single or multiple) and juvenile polyposis]

1
UI - 12010888
AU - Moisio AL; Jarvinen H; Peltomaki P
TI - Genetic and clinical characterisation of familial adenomatous polyposis: a population based study.
SO - Gut 2002 Jun;50(6):845-50
AD - Department of Medical Genetics, Biomedicum Helsinki, PO Box 63, FIN-00014 University of Helsinki, Finland. Anu-Liisa.Moisio@Helsinki.Fi
BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominantly inherited disease predisposing to colon cancer and caused by germline mutations in the APC (adenomatous polyposis coli) gene. AIMS: We conducted a population based study to evaluate the prevalence and clinical implications of APC mutations among Finnish FAP kindreds. A possible founder effect in parallel with previous observations in hereditary non-polyposis colon cancer (HNPCC) was addressed. PATIENTS: Affected individuals from 65 kindreds were included. METHODS: The APC gene was screened for mutations using the protein truncation test and heteroduplex analysis. Haplotype analysis was performed with four flanking microsatellite markers. Families that failed to show any mutations were scrutinised with Southern blot hybridisation and allelic expression analysis. RESULTS: Thirty eight different germline mutations in APC were identified in 47 kindreds (72%). The majority of these mutations were novel and unique to each family. Although sharing the classical polyposis phenotype, families without detectable APC mutations differed from mutation positive families in the following respects: firstly, mean age at polyposis diagnosis was higher (38.6 years (48 individuals) v 30.0 years (140 individuals); p=0.001); and secondly, the proportion of kindreds lacking extracolonic disease was higher (6/18 v. 5/47; p=0.04). CONCLUSIONS: Our results may pave the way for predictive testing in mutation positive families and should stimulate further molecular studies in mutation negative families. No founder effect was observed, which is in contrast with HNPCC in the same population.

2
UI - 12013617
AU - Andresen PA; Gedde-Dahl T Jr; Fausa O; Eide TJ; Heiberg A
TI - [Genetic analysis in familial adenomatous polyposis]
SO - Tidsskr Nor Laegeforen 2001 Jan 10;121(1):64-8
AD - Patologisk-anatomisk avdeling 9038 Regionsykehuset i Tromso. per.arne.andresen@rikshospitalet.no
BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder caused by germline mutations in the APC gene. FAP is characterised by a variable, but normally large number of colorectal adenomas and variations in extracolonic manifestations. These variations are associated with specific mutations of the APC gene. MATERIAL AND METHODS: Representatives from 70 Norwegian families are under molecular investigation. Analyses have so far been concentrated on the part of the APC gene associated with classic FAP. RESULTS: Germline mutations causing FAP have been identified in 36 of the 70 families examined. All mutations identified are confined to the first half of the gene and correlate to classic FAP. INTERPRETATION: Because of the mutation heterogeneity in FAP, the size of the APC gene and variations in phenotype, it is a laborious task to identify the causative mutations. Better approaches to the analysis of the whole APC have now been established and will result in a higher degree of mutation detection independent of phenotype. Family history and phenotype-genotype correlations are still important guidelines for efficient molecular genetic analysis of the APC gene. Genetic surveillance, personal and socio-economic benefits from presymptomatic and predictive testing of members of FAP families are discussed.

3
UI - 12057910
AU - Groves C; Lamlum H; Crabtree M; Williamson J; Taylor C; Bass S;
TI - Cuthbert-Heavens D; Hodgson S; Phillips R; Tomlinson I Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis.
SO - Am J Pathol 2002 Jun;160(6):2055-61
AD - Academic Unit and Polyposis Registry, Saint Mark's Hospital, Harrow, United Kingdom.
Studies of adenomatous polyposis coli (APC) mutations in familial adenomatous polyposis (FAP) have focused on large bowel disease. It has been found that: 1) germline APC mutations around codon 1300 are associated with severe colorectal polyposis; 2) somatic APC mutations in colorectal tumors tend to cluster approximately between codons 1250 and 1450; and 3) patients with germline mutations close to codon 1300 tend to acquire somatic mutations (second hits) in their colorectal polyps by allelic loss, whereas the tumors of other FAP patients have truncating second hits. Using new and published data, we have investigated how germline and somatic APC mutations influence the pathogenesis of upper gastrointestinal polyps in FAP. We have compared the results with those from colorectal disease. We found that somatic mutations in upper gastrointestinal polyps cluster approximately between codons 1400 and 1580. Patients with germline APC mutations after codon 1400 tend to show allelic loss in their upper gastrointestinal polyps; the tumors of other patients have truncating somatic mutations after codon 1400. Finally, patients with germline mutations after codon 1400 tend to have more severe duodenal polyposis (odds ratio, 5.72; 95% confidence interval, 1.13 to 28.89; P = 0.035). Thus, in both upper gastrointestinal and colorectal tumors, a specific region of the APC gene is associated with severe disease, clustering of somatic mutations, and loss of the wild-type allele. However, the region concerned is different in upper gastrointestinal and colorectal disease. The data suggest that loss of all APC SAMP repeats is probably necessary for duodenal and gastric tumorigenesis in FAP, as it is in colonic tumors. Compared with colonic tumors, however, retention of a greater number of beta-catenin binding/degradation repeats is optimal for tumorigenesis in upper gastrointestinal FAP.

4
UI - 11978511
AU - Liefers GJ; Tollenaar RA
TI - Cancer genetics and their application to individualised medicine.
SO - Eur J Cancer 2002 May;38(7):872-9
AD - Department of Surgery, K6R, Leiden University Medical Center, Leiden, The Netherlands. gjwillemijn@mindless.com
One of the great challenges of basic research is to translate scientific discoveries into the improved treatment of patients. For colorectal cancer, our increased understanding of the molecular aetiology of the disease has not yet been paralleled by an improvement in patient care. However, several new approaches are on the verge of clinical implementation. Technical advances such as real-time polymerase chain reaction (PCR) and microarray techniques coupled to insight in the molecular pathways in colorectal cancer makes it possible to develop new clinical tools for the diagnosis, classification and treatment of patients. The ultimate goal of the incorporation of cancer genetics into the clinical treatment of patients is individualised medicine; therapeutic strategies based on the molecular taxonomy of tumours and individually constructed for each patient.

5
UI - 11982717
AU - Leggett B
TI - When is molecular genetic testing for colorectal cancer indicated?
SO - J Gastroenterol Hepatol 2002 Apr;17(4):389-93
AD - Clinical Research Centre of the Royal Brisbane Hospital Research Foundation, Bancrift Centre, Herston 4029, Brisbane, Australia. barbara_leggett@health.qld.gov.au
The genetic mutations causing many of the syndromes which confer a high inherited risk of colorectal cancer have now been identified. These include familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, Peutz-Jeghers syndrome, Cowden's syndrome and juvenile polyposis. In all these diseases, the precise mutation is nearly always unique to a particular family; there are few mutation hot spots. This means that mutation detection is technically demanding. Nonetheless, genetic testing can now be used clinically to confirm the diagnosis in affected individuals, and to predict whether an "at risk" family member has inherited the disease and should therefore have endoscopic screening. Because current technology does not detect all mutations, a negative result in a definitely affected individual is diagnostically unhelpful and does not allow predictive testing of other family members. When a mutation can be detected, it is diagnostically very useful, and allows better management of all family members. Copyright 2002 Blackwell Publishing Asia Pty Ltd

6
UI - 12082030
AU - Fenton JI; Wolff MS; Orth MW; Hord NG
TI - Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc genotype.
SO - Carcinogenesis 2002 Jun;23(6):1065-70
AD - Department of Food Science and Human Nutrition, Michigan State University, 2110 Anthony Hall East Lansing, MI 48824, USA.
Colonic epithelial cell migration is required for normal differentiated cell function. This migratory phenotype is dependent upon wild-type adenomatous polyposis coli (Apc) expression. Non-tumorigenic murine colon epithelial cell lines with distinct Apc genotypes, i.e. young adult mouse colon (YAMC; Apc(+/+)) and immortomouse/Min colon epithelial (IMCE; Apc(Min/+) cells) were used to assess the association between the Apc genotype, cell motility and matrix metalloproteinase (MMP) activity. Cells were treated with epidermal growth factor (EGF; 1, 10 and 25 ng/ml), hepatocyte growth factor (HGF; 1, 10 and 25 ng/ml) and/or curcumin (0.1-100 microM). EGF (25 ng/ml) and HGF (25 ng/ml) induced a greater migratory response in YAMC compared with IMCE cells after 24 h (P < 0.05). Treatment with curcumin induced a greater or equivalent migratory response in IMCE than YAMC cells. When migrating cells were treated with Ilomastat (MMP inhibitor), migration was inhibited in both cell types. High concentrations of Ilomastat (25 and 50 microM) inhibited migration in both cell types, while low concentrations (10 microM) inhibited HGF-induced IMCE migration. Curcumin-induced migration was inhibited in both cell types at the highest concentration of Ilomastat (50 microM). Immuno-localization analysis of membrane type-1 (MT1)-MMP indicated that migration is associated with the redistribution of this protein from the endoplasmic reticulum to the plasma membrane. Addition of neutralizing polyclonal antibodies against MT1-MMP or a mixture of MT1, 2- and 3-MMPs demonstrated partial or complete inhibition of cell migration in both cell types, respectively. The data provide the first evidence that migration in non-tumorigenic murine colon epithelial cells is: (i) inducible by EGF and HGF in an Apc genotype-dependent manner, (ii) dependent on MT-MMP activity and (iii) inducible by curcumin in an Apc genotype-independent manner. The data suggest a potential mechanism by which curcumin may induce cells heterozygous for Apc to overcome defective cell migration, a phenotype associated with cell differentiation and apoptosis.

7
UI - 11568727
AU - Agnifili A; Schietroma M; Mattucci S; Carloni A; Caterino G; Rossi M;
TI - Pistoia MA; Carlei F [Polyps (single or multiple) and juvenile polyposis]
SO - Minerva Chir 2001 Oct;56(5):507-18
AD - Cattedra di Chirurgia Geriatrica, Universita degli Studi, L'Aquila, Italy.
The authors underline the important aspects of juvenile familial polyposis (JFP), a disease transmitted as an autosomal dominant trait. A case of JFP characterized by the presence of hundreds of polyps in the colo-rectal intestinal tract, is analyzed. The single juvenile polyp, multiple polyps (=/>5 polyps) and the sporadic form are examined. These are mucous hamartomas which can undergo neoplastic transformation (in carcinoma in 68% of untreated cases), a behaviour similar to that of adenomatous polyps. They differ from the later due to the following features: epidemiology (earlier appearance age), anatomopathology (stroma), clinical observation (self-recovery in some cases) and genetics (10q23.3-18q21, genetic mutations in a locus different those of adenomatous polyps). It is also necessary to determine its extension by means of colonoscopy, ileoscopy, gastroscopy and small bowel barium enema. Patients' screening through construction of the genealogical family tree is fundamental. Isolation of possible degenerative aspects of the polyps through biopsy is also fundamental. Single or multiple polyps are treated endoscopically, the juvenile polyposis is treated surgically (colectomy, total colectomy). A rigorous follow-up of the patients and their family members is recommended.

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