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NCI CANCERLIT^® Search: Familial Adenomatous Polyposis - September 2001

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Last Modified: November 1, 2001

• Qualitative and quantitative relationship between dysplastic aberrant crypt foci and tumorigenesis in the Min/+ mouse colon.

• [Digestive polyposes: genetic aspects]

• [Clinical follow-up and treatment of patients with familial adenomatous polyposis]

• Mouse models for human familial adenomatous polyposis.

• [Is there a role for rectal conservation in familial adenomatous polyposis?]

• Hepatoblastoma.

• Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations.

• Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis.

• Carcinogenesis: a balance between beta-catenin and APC.

• Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis.

• Oncogenic targets of beta-catenin-mediated transcription in molecular pathogenesis of intestinal polyposis.

CancerMail from the National Cancer Institute

1
UI - 21324318
AU - Paulsen JE; Steffensen IL; Loberg EM; Husoy T; Namork E; Alexander J
TI - Qualitative and quantitative relationship between dysplastic aberrant crypt foci and tumorigenesis in the Min/+ mouse colon.
SO - Cancer Res 2001 Jul 1;61(13):5010-5
AD - Department of Environmental Medicine, National Institute of Public Health, 0403 Oslo, Norway.
The multiple intestinal neoplasia (Min)/+ mouse, which harbors only one functional allele of the Apc gene, is susceptible to environmental factors that disrupt this gene and subsequently trigger Apc-driven tumorigenesis in the colon. Aberrant crypt foci (ACF) are assumed to be preneoplastic lesions in colon carcinogenesis. Recently, we reported the absence of "classical" ACF in the colon of untreated Min/+ mice. Instead we identified flat dysplastic lesions, which we denoted ACF(Min) (J. E. Paulsen et al., Scand. J. Gastroenterol., 35: 534-539, 2000). In contrast to the classical type, ACF(Min) are not elevated above the surrounding mucosa, and their detection is totally dependent on methylene blue staining and transillumination. In the present study, we treated Min/+ mice with 5 mg/kg body weight azoxymethane (AOM) at weeks 1 and 2 and demonstrated induction of both types of lesions. However, only ACF(Min) appeared to be associated with the development of adenomas. Monocryptal ACF(Min), large ACF(Min), and adenomas showed a uniform histopathological picture of dysplasia and cytoplasmic overexpression of beta-catenin, indicating a qualitative relationship between these lesions. Also a quantitative relationship was suggested because the dramatic decrease in ACF(Min) number from week 7 to 11 was paralleled by a reciprocal increase in tumor number, indicating fast-crypt multiplication of ACF(Min). In AOM-treated +/+ (wild-type) littermates, a low number of ACF(Min) and tumors with the same characteristics as in Min/+ mice was seen. In contrast to ACF(Min), histopathological and immunohistochemical examination of classical ACF showed normal or hyperplastic crypts with normal levels of beta-catenin expression. In AOM-treated Min/+ mice, the number of classical ACF was virtually constant from week 7 to 11, and only a modest increase of crypt multiplicity was observed. The number of AOM-induced classical ACF at week 11 was not different in Min/+ mice and +/+ mice. In conclusion, we identified two distinct populations of altered crypts in the colon of Min/+ mice after AOM treatment. The ACF(Min), which resemble the dysplastic ACF described previously, clearly showed a continuous development from the monocryptal stage to adenoma, and they were characterized by fast-growing crypts with altered control of beta-catenin. In contrast, the classical ACF, which resemble the hyperplastic ACF described previously, were characterized by slow-growing crypts with normal beta-catenin expression, and they were probably not related to tumorigenesis.

2
UI - 21341877
AU - Olschwang S
TI - [Digestive polyposes: genetic aspects]
SO - Gastroenterol Clin Biol 2001 Apr;25(4 Suppl):B26-30
AD - INSERM U434, Fondation Jean-Dausset-CEPH, 27, rue Juliette-Dodu, 75010 Paris.

3
UI - 21341878
AU - Saurin JC
TI - [Clinical follow-up and treatment of patients with familial adenomatous polyposis]
SO - Gastroenterol Clin Biol 2001 Apr;25(4 Suppl):B31-7
AD - Federation des Specialites Digestives, Hopital Edouard-Herriot, 5, place d'Arsonval, 69437 Lyon Cedex 03.

4
UI - 21302029
AU - Kucherlapati R; Lin DP; Edelmann W
TI - Mouse models for human familial adenomatous polyposis.
SO - Semin Cancer Biol 2001 Jun;11(3):219-25
AD - Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. kucherla@aecom.yu.edu
Colorectal cancer (CRC) is the second most frequent type of cancer in the Western hemisphere. In the United States alone, it is estimated that 150 000 new cases are detected every year and more than 65 000 patients die from complications associated with this cancer. Identification of genes implicated in the initiation and progression of colorectal cancer in humans has prompted the generation of mouse models for this cancer. We will provide a brief overview of these mouse models for CRC and what they have contributed to our understanding of the events involved in the initiation and progression of this cancer. Copyright 2001 Academic Press.

5
UI - 21421624
AU - Villar F; Buecher B; Lehur PA
TI - [Is there a role for rectal conservation in familial adenomatous polyposis?]
SO - Gastroenterol Clin Biol 2001 May;25(5):559-60
AD - Clinique Chirurgicale II, Centre Hospitalo-Universitaire de Nantex, Place Alexic-Ricordeau, BP 1005, 44093 Nantes Cedex 01, France.

6
UI - 21220191
AU - Berdon WE
TI - Hepatoblastoma.
SO - Pediatr Radiol 2001 Apr;31(4):306

7
UI - 21249648
AU - Wirtzfeld DA; Petrelli NJ; Rodriguez-Bigas MA
TI - Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations.
SO - Ann Surg Oncol 2001 May;8(4):319-27
AD - Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, 14263, USA.
Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur. Juvenile polyposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene (18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-beta) signal transduction. The increased neoplastic risk may result from SMAD-4 mutations in the stromal component, which stimulate epithelial dysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJS) is associated with germ-line mutations in the LKB1 gene (19p13.3) that encodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Patients are at an increased risk of intestinal and extraintestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden's disease is associated with germ-line mutations in the PTEN gene (10q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden's disease. Conclusions: Genetic alterations underlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may result from either germ-line mutations in the stroma (JPS) or as a direct result of functional deletion of tumor suppressor genes (PJS). Diagnosis depends on clinical presentation and patterns of inheritance within families. Suggested surveillance guidelines for the proband and first-degree relatives are outlined.

8
UI - 21413768
AU - Takayama T; Ohi M; Hayashi T; Miyanishi K; Nobuoka A; Nakajima T; Satoh T; Takimoto R; Kato J; Sakamaki S; Niitsu Y
TI - Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis.
SO - Gastroenterology 2001 Sep;121(3):599-611
AD - Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
BACKGROUND & AIMS: We have previously shown that aberrant crypt foci (ACF) are the putative precursor lesions of colorectal adenomas and subsequent cancer in humans using magnifying endoscopy. The present study was designed to investigate these genetic alterations in ACF biopsy specimens from normal subjects, familial adenomatous polyposis (FAP) or sporadic patients. METHODS: The non-FAP cases included 34 normal subjects, 35 colorectal adenoma patients, and 19 colorectal cancer patients; there were 4 FAP patients. Biopsies were performed on ACF by magnifying endoscopy. K-ras mutations were analyzed by 2-step polymerase chain reaction and restriction fragment length polymorphism, APC mutations by in vitro-synthesized protein assay, and beta-catenin mutations by direct sequencing. Full-length APC and beta-catenin were detected by immunofluorescence. RESULTS: In non-FAP cases, K-ras mutations were detected in 82% (89/106) of nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC mutation and beta-catenin accumulation were not detected in non-FAP ACF, whereas in adenoma of these patients, positivity of APC mutation and beta-catenin accumulation were 78% (24/31), and that of K-ras mutation was 65% (20/31). FAP patients showed K-ras mutations in only 13% (1/8) of dysplastic ACF, which is the predominant form of ACF found in FAP. In FAP patients, somatic APC mutations were found in 100% of dysplastic ACF, as they are in adenoma. The frequency of K-ras mutations was 73% (8 of 11) in FAP adenoma. CONCLUSIONS: The data suggest that in sporadic colorectal carcinogenesis, assuming the biological implication of ACF as a precursor of adenomas, there is a route where K-ras mutation mainly occurs during the formation of ACF, which then become adenomas wherein APC mutation occurs. In FAP, however, somatic mutation of APC predominantly occurs during ACF formation, followed by K-ras mutation.

9
UI - 97362381
AU - Gumbiner BM
TI - Carcinogenesis: a balance between beta-catenin and APC.
SO - Curr Biol 1997 Jul 1;7(7):R443-6
AD - Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, Box 564, 1275 York Avenue, New York, New York 10021, USA. b-gumbiner@ski.mskcc.org
A protein first identified by its association with cadherin cell adhesion molecules, beta-catenin, has been implicated in carcinogenesis. In a number of different types of cancer, signalling through beta-catenin is upregulated either by direct mutation of beta-catenin or loss of negative regulation by the APC tumor suppressor protein.

10
UI - 21426724
AU - Guldenschuh I; Hurlimann R; Muller A; Ammann R; Mullhaupt B; Dobbie Z; Zala GF; Flury R; Seelentag W; Roth J; Meyenberger C; Fried M; Hoppeler T; Spigelman AD; Scott RJ
TI - Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis.
SO - Dis Colon Rectum 2001 Aug;44(8):1090-7; discussion 1097-9
AD - Gastroenterology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
PURPOSE: Familial adenomatous polyposis is an inherited colorectal cancer syndrome characterized by the presence of multiple adenomatous colorectal polyps. Molecular studies have revealed that germline mutations in the APC gene are the underlying cause of the disease. The nonsteroidal anti-inflammatory agent sulindac has been shown to reduce the number of colorectal adenomas. Most sulindac trials in the large bowel have focused on the distal colon and relatively little is known about its effect on the proximal colon. Moreover, it is unknown whether the site of the APC mutation affects the efficacy of sulindac. METHODS: This study investigated whether there were regional differences in the effect of sulindac on the colon and whether response to sulindac was dependent on the site of mutation in the APC gene. In an open prospective study 17 patients with familial adenomatous polyposis were treated with 300 mg oral sulindac daily for four months followed by a washout phase of six months. Ten of the patients had an intact colon and seven had rectal stumps only. The number, size, and the degree of dysplasia of the adenomas were evaluated by colonoscopy at entry, end of treatment and end of the study. RESULTS: Overall, a statistically significant decrease in the number of adenomas was observed (120 +/- 112 to 28 +/- 64, P = 0.007). After cessation of sulindac treatment the number of adenomas increased to 48 +/- 44.5, but remained significantly lower than the values observed at baseline. In the ten patients with intact colons, adenomas decreased by sevenfold in the proximal colon (103 +/- 73 to 15.1 +/- 47.4, P = 0.011) and twofold in the distal colon (80 +/- 52 to 29.6 +/- 37.2, P = 0.005). The size of adenomas and the grade of dysplasia also decreased. No correlation could be seen between the APC mutation site and the response to treatment. CONCLUSION: These data indicate that sulindac reduces the number of adenomas in the entire colon and that the effect seems to be more pronounced in the proximal colon.

11
UI - 21442181
AU - Watson SA
TI - Oncogenic targets of beta-catenin-mediated transcription in molecular pathogenesis of intestinal polyposis.
SO - Lancet 2001 Feb 24;357(9256):572-3
AD - Academic Unit of Cancer Studies, University of Nottingham, UK. sue.watson@nottingham.ac.uk