National Cancer Institute®
Last Modified: April 1, 2002
UI - 11552476
AU - Carlomagno N; Scarano MI; Gargiulo S; De Rosa M; Panariello L; Izzo P;
TI - Renda A [Familial colonic polyposis: effect of molecular analysis on the diagnostic-therapeutic approach]
SO - Ann Ital Chir 2001 Mar-Apr;72(2):207-14
AD - Chirurgia Generale ad Indirizzo Addominale, Universita Federico II, Napoli. firstname.lastname@example.org
Germline mutations of the Adenomatous polyposis gene (APC) are responsible for Familial Adenomatous Polyposis (FAP), an inherited condition that predisposes to the development of hundreds to thousands benign adenomas in the colo-rectum. If not surgically removed, they inevitably progress into malignant adenocarcinoma. To date more than 450 germline mutations have been described allowing the establishment of genotype/phenotype correlation between the site and type of molecular defects and their morbid consequences. Authors reviewed their experience concerning 22 FAP affected patients and their 26 first degree relatives, in whom the mutational analysis of the APC gene had been carried out. Site and type of mutations were associated with clinical parameters (age of onset, rectal involvement, extracolonic manifestations, presence of colorectal cancer) and treatments. The impact of mutational analyses on the clinical approach could be very interesting in the future, modifying both surveillance programs and therapeutical choices.
UI - 11905639
AU - Jass J R
TI - Familial colorectal cancer: pathology and molecular characteristics.
SO - Lancet Oncol 2000 Dec;1():220-6
AD - Department of Pathology, University of Queensland, Mayne Medical School, Herston, Australia. email@example.com
Appropriate management of familial colorectal cancer revolves around the diagnosis of the underlying genetic syndrome. This necessitates an interdisciplinary approach allowing integration of clinical, morphological, and molecular evidence that may involve several members of the same family. Genetic disorders express themselves over time, whereas clinical investigation of family members is likely to be episodic. Generic features of hereditary colorectal cancer syndromes include a positive family history, early age at onset, multiple neoplasms, and extracolonic lesions of either a developmental or neoplastic nature. Deriving a complete description of a genetic disorder is hampered by the need to trace and obtain tissue samples from many institutions. This review examines the usefulness of tissue-based investigations, both morphological and molecular, in raising the suspicion of familial colorectal cancer, providing a definitive tissue diagnosis and contributing to the larger body of diagnostic evidence. The account focuses on the two most well-studied syndromes--familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC)--but consideration is also given to less well-understood syndromes. Some of these, notably hyperplastic polyposis and mixed polyposis, may closely mimic FAP or HNPCC.
UI - 11899542
AU - Krutilkova V; Havlovicova M; Goetz P
TI - [Specialized genetic counseling in pediatric and adult oncology patients]
SO - Cas Lek Cesk 2002;141(1):23-7
AD - Ustav biologie a lekarske genetiky 2. LF UK a FNM, Praha. firstname.lastname@example.org
Five to ten percent of oncological diseases exhibit monogenic mode of inheritance. They occur as a consequence of the germline mutations of tumor suppressor genes and of the genes engaged in reparative processes. Most common monogenically determined oncological diseases are: AD form of breast and ovarian cancer, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch sy.) and familiar adenomatous polyposis (FAP). The aim of the genetic investigation is to evaluate whether the index family deals with the hereditary form of tumor predisposition, than, if possible, to perform DNA analysis in the family and to propose preventive screening program (methods) for the probands in risk.
UI - 11809680
AU - Cheadle JP; Krawczak M; Thomas MW; Hodges AK; Al-Tassan N; Fleming N;
TI - Sampson JR Different combinations of biallelic APC mutation confer different growth advantages in colorectal tumours.
SO - Cancer Res 2002 Jan 15;62(2):363-6
AD - Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
New facets to Knudson's [corrected] "two-hit" hypothesis have been proposed recently in relation to adenomatous polyposis coli (APC): protein inactivation may be selected weakly, and the two hits may be interdependent. We reviewed published data on 165 sporadic and 102 familial adenomatous polyposis-associated colorectal tumors with two characterized mutations. Using a Poisson model, we redefined the mutation cluster region (MCR) to residues 1281-1556 and confirmed that the locations of pairs of APC mutations are interdependent (P < 0.0001). A mathematical model, based on the data for sporadic tumors, implied different growth advantages for different combinations of APC mutations: genotype I/I (I: mutation inside MCR) was 3.9 times more likely to be selected than IO or IL (O: mutation outside MCR, L: allelic loss), which were 27.8 times more likely to be selected than OO or OL.
UI - 11113066
AU - Bulow C; Vasen H; Jarvinen H; Bjork J; Bisgaard ML; Bulow S
TI - Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis.
SO - Gastroenterology 2000 Dec;119(6):1454-60
AD - Danish Polyposis Register, Hvidovre University Hospital, Copenhagen, Denmark.
BACKGROUND & AIMS: This study reevaluates the risk of rectal cancer and the frequency of subsequent proctectomy for nonmalignant causes in patients with familial adenomatous polyposis (FAP) who have undergone colectomy with ileorectal anastomosis (IRA). Potential risk factors for rectal cancer in this setting are also examined, and recommendations for the choice of surgical procedure are made. METHODS: The national polyposis registries in Denmark, Finland, The Netherlands, and Sweden included 659 patients undergoing surgery with IRA in 1940-1997. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate cumulative risk, survival, and predictive risk factors. RESULTS: Rectal carcinoma was diagnosed in 47 patients, with a cumulative 40-year risk of 0.32. The cumulative risk according to chronologic age was 0.30 at age 60, and higher in patients undergoing surgery above age 25 (P = 0.0016). Chronologic age was the only independent risk factor (P = 0.0016). The cumulative 5-year survival rate after rectal carcinoma was 0.60. The apc mutation was known in 167 patients, of whom 7 had rectal cancer. The cumulative 40-year risk of secondary proctectomy was 0.70, and higher in patients with a mutation in codon 1250-1500 than outside this region (P = 0.005). However, all 7 rectal cancers were found in the latter group. None of the 18 patients with attenuated FAP (mutation in codon 0-200 or >1500) had a secondary proctectomy. CONCLUSIONS: IRA is recommended in (1) young patients with few rectal adenomas and a family history of a mild phenotype and (2) patients with attenuated FAP (a mutation in codon 0-200 or >1500), provided there is acceptance of life-long rectal surveillance. Patients with many rectal polyps and/or a family history of severe polyposis should be offered a restorative proctocolectomy with an ileal pouch-anal anastomosis.
UI - 11494977
AU - Friedl W; Mangold E; Caspari R; Lamberti C; Propping P
TI - Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis.
SO - Gastroenterology 2001 Aug;121(2):503-4
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 - 11868006
AU - Saurin JC; Ligneau B; Ponchon T; Lepretre J; Chavaillon A; Napoleon B;
TI - Chayvialle JA The influence of mutation site and age on the severity of duodenal polyposis in patients with familial adenomatous polyposis.
SO - Gastrointest Endosc 2002 Mar;55(3):342-7
AD - Federation des specialites digestives, Laboratoire de genetique, Hopital E. Herriot, 5 place d'Arsonval, 64937 Lyon Cedex 03, France.
BACKGROUND: The present study was undertaken to identify factors affecting the severity of the duodenojejunal polyposis in patients with familial adenomatous polyposis. METHODS: Duodenojejunal polyposis was evaluated in 41 consecutive patients with familial adenomatous polyposis (mean age 41 years, range 21-63 years), 33 (80%) with known APC mutation, by using a standardized endoscopic protocol. The severity of the polyposis was graded with the Spigelman scoring system (0-12 points), the Spigelman score/age ratio, and the presence or absence of advanced adenomas (>1 cm in diameter and/or high-grade dysplasia). RESULTS: The Spigelman score (median 8, range 3-12) was higher in patients older than 50 years (median 10, range 3-12) as compared with younger patients (median 7.5, range 3-11; p = 0.043). A significant association between age and the presence of advanced adenomas was also observed. Patients with a mutation in the central part of the APC gene (codons 279-1309) had a higher Spigelman score and Spigelman score/age ratio as compared with patients with other mutations: median Spigelman score/age ratio 0.21 (range 0.14-0.40) versus 0.10 (range 0.06-0.20) (p < 0.001). CONCLUSIONS: Older age and APC mutation in the central part of the gene are risk factors for the development of severe duodenojejunal polyposis.
UI - 10223463
AU - Taylor MD; Perry J; Zlatescu MC; Stemmer-Rachamimov AO; Ang LC; Ino Y;
TI - Schwartz M; Becker LE; Louis DN; Cairncross JG The hPMS2 exon 5 mutation and malignant glioma. Case report.
SO - J Neurosurg 1999 May;90(5):946-50
AD - Department of Medicine, University of Toronto, Ontario, Canada.
Patients with Turcot syndrome (TS) are predisposed to colon tumors and primary brain tumors, typically glioblastomas or medulloblastomas. The authors describe a patient with TS featuring a known germline mutation of exon 5 of the hPMS2 mismatch repair gene who developed two metachronous glioblastomas, both with distinct oligodendroglial features. Molecular genetic analysis revealed allelic loss of chromosome 19q in the patient's second tumor but no allelic loss of chromosome 1p. Prominent microsatellite instability was also found in this tumor, consistent with a germline mismatch repair defect. Because this patient had an unusual underlying condition and his tumor had a unique histological appearance for TS, it was hypothesized that this genetic defect may predispose to malignant gliomas with oligodendroglial features. The authors therefore evaluated whether sporadic glioblastomas and oligodendrogliomas undergo mutations of this region of the hPMS2 gene. However, single-strand conformation polymorphism analysis of hPMS2 exon 5 failed to reveal mutations in 20 sporadic glioblastomas and 16 sporadic oligodendroglial gliomas. Thus, although it is possible that the germline hPMS2 exon 5 mutation may predispose to glioblastomas with an oligodendroglial component, the same genetic defect is not commonly involved in sporadic oligodendrogliomas or glioblastomas.
UI - 10536173
AU - Arai T; Akiyama Y; Nagasaki H; Murase N; Okabe S; Ikeuchi T; Saito K;
TI - Iwai T; Yuasa Y EXTL3/EXTR1 alterations in colorectal cancer cell lines.
SO - Int J Oncol 1999 Nov;15(5):915-9
AD - First Department of Surgery, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
We previously demonstrated that metastasis-related tumor suppressor gene(s) may exist on chromosome 8p21-22 on allelotype analysis of early colorectal carcinomas (CRC) with lymph node metastasis. Here, we searched for target gene(s) in this chromosomal region in the UniGene database. The EXTL3 (also called EXTR1) gene was selected as a candidate because of its homology to EXT1 and EXT2, putative tumor suppressor genes. We screened 12 CRC cell lines for mutations by means of polymerase chain reaction (PCR)-single strand conformation polymorphism. Three cell lines showed EXTL3 mutations, all of which were located within exon 3 and caused amino acid substitutions. Reverse transcription-PCR analysis showed that the EXTL3 expression was lacking in 1 of the 12 colorectal cancer cell lines. Although there is still no definitive evidence that EXTL3 is a tumor suppressor gene for CRC, these data suggest that inactivation of the EXTL3 gene may at least offer a selective growth advantage for some CRC cell lines.
UI - 10965758
AU - Matsumoto T; Iida M
TI - [Genetic aspects of hereditary polyposis of the gastrointestinal tract]
SO - Nippon Shokakibyo Gakkai Zasshi 2000 Aug;97(8):1007-16
AD - Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital.
UI - 11244511
AU - Tan C; Costello P; Sanghera J; Dominguez D; Baulida J; de Herreros AG;
TI - Dedhar S Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC-/- human colon carcinoma cells.
SO - Oncogene 2001 Jan 4;20(1):133-40
AD - BC Cancer Agency and Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
Loss of functional adenomatous polyposis coli (APC) protein results in the stabilization of cytosolic beta-catenin and activation of genes that are responsive to Lef/Tcf family transcription factors. We have recently shown that an independent cell adhesion and integrin linked kinase (ILK)-dependent pathway can also activate beta-catenin/LEF mediated gene transcription and downregulate E-cadherin expression. In addition, ILK activity and expression are elevated in adenomatous polyposis and colon carcinomas. To examine the role of this pathway in the background of APC mutations we inhibited ILK activity in APC-/- human colon carcinoma cell lines. In all cases, inhibition of ILK resulted in substantial inhibition of TCF mediated gene transcription and inhibition of transcription and expression of the TCF regulated gene, cyclin D1. Inhibition of ILK resulted in decreased nuclear beta-catenin expression, and in the inhibition of phosphorylation of GSK-3 and stimulation of its activity, leading to accelerated degradation of beta-catenin. In addition, inhibition of ILK suppressed cell growth in culture as well as growth of human colon carcinoma cells in SCID mice. Strikingly, inhibition of ILK also resulted in the transcriptional stimulation of E-cadherin expression and correlated with the inhibition of gene transcription of snail, a repressor of E-cadherin gene expression. Overexpression of ILK caused a stimulation of expression of snail, but snail expression was found not to be regulated by beta-catenin/Tcf. These data demonstrate that ILK can regulate beta-catenin/TCF and snail transcription factors by distinct pathways. We propose that inhibition of ILK may be a useful strategy in the control of progression of colon as well as other carcinomas. Oncogene (2001) 20, 133 - 140.
UI - 11381269
AU - Howe JR; Bair JL; Sayed MG; Anderson ME; Mitros FA; Petersen GM;
TI - Velculescu VE; Traverso G; Vogelstein B Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.
SO - Nat Genet 2001 Jun;28(2):184-7
AD - Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa, USA. email@example.com
Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families. However, mutations in MADH4 are only present in a subset of JP cases, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families, undefined genetic heterogeneity remains. Using a genome-wide screen in four JP kindreds without germline mutations in MADH4 or PTEN, we identified linkage with markers from chromosome 10q22-23 (maximum lod score of 4.74, straight theta=0.00). We found no recombinants using markers developed from the vicinity of the gene for bone morphogenetic protein receptor 1A (BMPR1A), a serine-threonine kinase type I receptor involved in bone morphogenetic protein (BMP) signaling. Genomic sequencing of BMPR1A in each of these JP kindreds disclosed germline nonsense mutations in all affected kindred members but not in normal control individuals. These findings indicate involvement of an additional gene in the transforming growth factor-beta (TGF-beta) superfamily in the genesis of JP, and document an unanticipated function for BMP in colonic epithelial growth control.
UI - 11355940
AU - Woodford-Richens KL; Halford S; Rowan A; Bevan S; Aaltonen LA; Wasan H;
TI - Bicknell D; Bodmer WF; Houlston RS; Tomlinson IP CDX2 mutations do not account for juvenile polyposis or Peutz-Jeghers syndrome and occur infrequently in sporadic colorectal cancers.
SO - Br J Cancer 2001 May 18;84(10):1314-6
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, London, WC2A 3PX, UK.
Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JPS) are both characterized by the presence of hamartomatous polyps and increased risk of malignancy in the gastrointestinal tract. Mutations of the LKB1 and SMAD4 genes have been shown recently to cause a number of PJS and JPS cases respectively, but there remains considerable uncharacterized genetic heterogeneity in these syndromes, particularly JPS. The mouse homologue of CDX2 has been shown to give rise to a phenotype which includes hamartomatous-like polyps in the colon and is therefore a good candidate for JPS and PJS cases which are not accounted for by the SMAD4 and LKB1 genes. By analogy with SMAD4, CDX2 is also a candidate for somatic mutation in sporadic colorectal cancer. We have screened 37 JPS families/cases without known SMAD4 mutations, 10 Peutz-Jeghers cases without known LKB1 mutations and 49 sporadic colorectal cancers for mutations in CDX2. Although polymorphic variants and rare variants of unlikely significance were detected, no pathogenic CDX2 mutations were found in any case of JPS or PJS, or in any of the sporadic cancers. Copyright 2001 Cancer Research Campaign.
UI - 11593435
AU - Marotta A; Tan C; Gray V; Malik S; Gallinger S; Sanghera J; Dupuis B;
TI - Owen D; Dedhar S; Salh B Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis.
SO - Oncogene 2001 Sep 27;20(43):6250-7
AD - Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dysregulation of beta-catenin are well-documented abnormalities in familial adenomatous polyposis (FAP), as well as sporadic polyposis. Intriguingly, overexpression of the integrin-linked kinase (ILK) has been shown to modulate beta-catenin subcellular localization and function. However, the significance of this finding for human carcinogenesis remains unclear. Here, we report the increased biochemical activity and expression of ILK protein in polyps from FAP patients. Furthermore, dramatic increases in ILK immunoreactivity were observed in all abnormal crypts from sporadic polyps, when compared with the normal appearing crypts within the same resected specimens. As sulindac and aspirin are the two most important therapeutic/chemopreventative agents demonstrated in colorectal carcinogenesis, in both humans and animals, further investigation revealed that these non-steroidal anti-inflammatory drugs (NSAIDs) target ILK and ILK-mediated events in vivo. These include inhibition of, both the biochemical activation of ILK, inhibition of serine 9 GSK3beta phosphorylation and the enhancement of TCF-4 transcriptional activity. In conclusion, ILK protein hyperexpression appears to be an early event in colonic polyposis. Additionally, ILK signaling is shown to undergo modulation by sulindac (and aspirin) for the first time, indicating that it is likely to be one of the targets affected by these agents in vivo.
UI - 11896466
AU - Fuerer C; Iggo R
TI - Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway.
SO - Gene Ther 2002 Feb;9(4):270-81
AD - Oncogene Group, Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland.
Mutation of the adenomatous polyposis coli and beta-catenin genes in colon cancer leads to constitutive activation of transcription from promoters containing binding sites for Tcf/LEF transcription factors. We have constructed adenoviruses with Tcf binding sites in the early promoters, in order to target viral replication to colon tumours. Tcf regulation of the E1A promoter confers a 100-fold selectivity for cells with activated wnt signalling in viral burst and cytopathic effect assays. p300 is a coactivator for beta-catenin, and E1A inhibits Tcf-dependent transcription through sequestration of p300, but mutation of the p300 binding site in E1A leads to a 10-fold reduction in cytopathic effect of all of the Tcf-regulated viruses. When Tcf sites are inserted in the E1A, E1B, E2 and E4 promoters the viruses show up to 100 000-fold selectivity for cells with activated wnt signalling.
UI - 11922570
AU - Batra S; Valdimarsdottir H; McGovern M; Itzkowitz S; Brown K
TI - Awareness of genetic testing for colorectal cancer predisposition among specialists in gastroenterology.
SO - Am J Gastroenterol 2002 Mar;97(3):729-33
AD - Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.
OBJECTIVES: Adult gastroenterologists practicing in New York State were surveyed to determine their practice with regard to identifying family histories consistent with inherited forms of colorectal cancer, and to assess their awareness of cancer genetic counseling and molecular genetic testing for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: A closed-ended questionnaire was mailed to 815 gastroenterologists identified through the membership Directory of the American Gastroenterological Association (1998). Two mailings resulted in a response rate of 35%. RESULTS: In all, 99% of the gastroenterologists obtained a family history from their patients, and 95% were aware of cancer genetic counseling. However, only 51% would routinely refer patients for genetic counseling before providing cancer predisposition testing. In addition, only 52% were aware of the availability of genetic tests for FAP and 34% for HNPCC. Presented with a family history consistent with HNPCC, 79% could identify the syndrome, 26% recommended genetic counseling for the consultand, and 16% advised appropriate screening, according to current recommendations. CONCLUSIONS: The majority of gastroenterologists do obtain a family history on their patients. However, there is a need for physician education regarding the recognition of pedigrees consistent with inherited colorectal cancer, the genetic counseling process, and the availability of mutation testing for FAP and HNPCC.
UI - 11889072
AU - Hardy RG; Tselepis C; Hoyland J; Wallis Y; Pretlow TP; Talbot I; Sanders
TI - DS; Matthews G; Morton D; Jankowski JA Aberrant P-cadherin expression is an early event in hyperplastic and dysplastic transformation in the colon.
SO - Gut 2002 Apr;50(4):513-9
AD - Department of Surgery, University of Birmingham, Birmingham, UK. firstname.lastname@example.org
BACKGROUND: Colorectal adenomatous and, probably, hyperplastic polyp development requires epithelial remodelling and stratification, with loss of E-cadherin expression implicated in adenoma formation. We have shown that P-cadherin, normally expressed in stratified epithelia and placenta, is aberrantly expressed in disturbed epithelial architecture associated with colitis. AIMS: (i) To investigate the role of P-cadherin in colonic polyp formation. (ii) To ascertain whether expression of P-cadherin is independent of or correlated with expression of its associated proteins--E-cadherin, beta-catenin, and gamma-catenin. (iii) To determine if P-cadherin is functional regarding catenin binding in polyps. METHODS: Expression and localisation of cadherins (E- and P-) and their associated catenins (beta- and gamma-) were determined in aberrant crypt foci (ACF), in polyps with hyperplastic morphology (hyperplastic polyps and serrated adenomas), and in adenomatous polyps by immunohistochemistry, western blotting, and mRNA in situ hybridisation. Assessment of cadherin-catenin binding was evaluated by co-immunoprecipitation. Adenomatous polyposis coli (APC) mutation was assessed in adenomatous polyps. RESULTS: P-cadherin was expressed from ACF through to hyperplastic and adenomatous polyps. Alterations in E-cadherin and catenin expression occurred later, with variant patterns in (i) ACF, (ii) hyperplastic polyps and serrated adenomas, and (iii) adenomatous polyps. P-cadherin present in adenomas was functional with regard to catenin binding, and its expression was independent of APC mutational status. CONCLUSIONS: P-cadherin is aberrantly expressed from the earliest morphologically identifiable stage of colonocyte transformation, prior to changes in E-cadherin, catenin, and APC expression/mutation. P-cadherin expression alone does not predict tissue morphology, and such expression is independent of that of associated cadherins and catenins.
UI - 11957250
AU - Wakhisi J
TI - Lessons learned from colorectal model of tumourigenesis.
SO - East Afr Med J 2001 Jul;78(7 Suppl):S48-9
AD - Department of Medical Biochemistry, Faculty of Health Sciences, Moi University, P.O. Box 3900, Eldoret, Kenya.
Genetic analytical techniques were carried out to identify mutations in adenomatous polyposis coli (APC) gene and K-ras oncogene in colorectal tumourigenesis. These two genes are said to be early mutation genes among other mutation genes that constitute the model for colorectal tumourigenesis. To do this analysis, DNA was isolated from colorectal formalin fixed paraffin-embedded tumour tissue sections. The sections were deparaffinised, digested in proteinase-K, followed by DNA isolation. The DNA was amplified by Polymerase Chain Reaction (PCR), screened by using Denaturing Gradient Gel Electrophoresis (DGGE) or Single Strand Conformation Polymorphism (SSCP) and then sequenced. These results lend support to the fact that colorectal cancer and indeed cancer in general develops through a multi-step process; also that accumulation of genetic mutations underlie the development of neoplasia. We are in the process of extending this study to cancer of oesophagus to see if a similar or parallel model of carcinogenesis holds and in what sequence it is.
UI - 11896079
AU - Young J; Barker M; Robertson T; Nasioulas S; Tannenberg A; Buttenshaw
TI - RL; Knight N; Jass JR; Leggett BA A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis.
SO - J Clin Pathol 2002 Mar;55(3):230-1
AD - Conjoint Gastroenterology Laboratory, Clinical Research Centre, Royal Brisbane Hospital Research Foundation, Bancroft Centre, 300 Herston Road, Herston Q4029, Australia.
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.
UI - 10359544
AU - Potter JD
TI - Colorectal cancer: molecules and populations.
SO - J Natl Cancer Inst 1999 Jun 2;91(11):916-32
AD - Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. email@example.com
The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
UI - 11867715
AU - Sieber OM; Lamlum H; Crabtree MD; Rowan AJ; Barclay E; Lipton L; Hodgson
TI - S; Thomas HJ; Neale K; Phillips RK; Farrington SM; Dunlop MG; Mueller HJ; Bisgaard ML; Bulow S; Fidalgo P; Albuquerque C; Scarano MI; Bodmer W; Tomlinson IP; Heinimann K Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas.
SO - Proc Natl Acad Sci U S A 2002 Mar 5;99(5):2954-8
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.
UI - 10614178
AU - Taketo MM
TI - [Intestinal polyposis in APC knockout mice: mechanism of tumorigenesis and chemotherapy]
SO - Seikagaku 1999 Nov;71(11):1299-308
AD - Laboratory of Biomedical Genetics, Graduate School Pharmaceutical Science, University of Tokyo.
UI - 11953860
AU - Chiang JM; Chou YH; Chen TC; Ng KF; Lin JL
TI - Nuclear beta-catenin expression is closely related to ulcerative growth of colorectal carcinoma.
SO - Br J Cancer 2002 Apr 8;86(7):1124-9
AD - Division of Colon and Rectal Surgery, Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan 333. firstname.lastname@example.org
Although most colorectal cancer develops based on the adenoma-adenocarcinoma sequence, morphologically, colorectal cancer is not a homogeneous disease entity. Generally, there are two distinct morphological types: polypoid and ulcerative colorectal tumours. Previous studies have demonstrated that K-ras codon 12 mutations are preferentially associated with polypoid growth of colorectal cancer; however, little is known about the molecular mechanism that determines ulcerative growth of colorectal cancer. beta-catenin complex plays a critical role both in tumorigenesis and morphogenesis. We examined the differential expression of beta-catenin and its related factors among different types of colorectal cancer in order to determine any relationship with gross tumour morphology. Immunohistochemical staining of beta-catenin, E-cadherin and MMP-7 was performed on 51 tumours, including 26 polypoid tumours and 25 ulcerative tumours. Protein truncation tests and single-strand conformational polymorphism for mutation of the adenomatous polyposis coli tumour suppressor gene, as well as single-strand conformational polymorphism for the mutation of beta-catenin exon 3 were also done. Nuclear expression of beta-catenin was observed in 18 out of 25 (72%) cases of ulcerative colorectal cancer and seven out of 26 (26.9%) cases of polypoid colorectal cancer. A significant relationship of nuclear beta-catenin expression with ulcerative colorectal cancer was found (P<0.001). However, this finding was independent of adenomatous polyposis coli tumour suppressor gene mutation and E-cadherin expression. Together with previous data, we propose that different combinations of genetic alterations may underlie different morphological types of colorectal cancer. These findings should be taken into consideration whenever developing a new genetic diagnosis or therapy for colorectal cancer.
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