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PubMed2004

Comprehensive genetic and endoscopic evaluation may be necessary to distinguish sporadic versus familial adenomatous polyposis-associated abdominal desmoid tumors.

BACKGROUND: There are limited data regarding how many patients with desmoid tumors actually represent cases with underlying familial adenomatous polyposis. METHODS: A proband presenting with desmoid tumors and several of the family members underwent a detailed family history, genetic (adenomatous polyposis coli [APC] gene sequencing), and upper and lower endoscopic evaluation. RESULTS: The proband's initial diagnosis was of a sporadic desmoid tumor. Colonoscopy was entirely normal. However, on subsequent esophagogastroduodenoscopy, several gastric polyps were found. The proband's mother subsequently underwent colonoscopy and was found to have multiple colon adenomas. On genetic analysis, a deletion of "T" was identified at codon 2645 of the APC gene in the proband. The proband's mother had a normal APC protein truncation test result. However, on full gene sequencing, the mother was found to harbor the same APC gene mutation. CONCLUSION: A detailed family history and endoscopic and genetic evaluations for patients with desmoid tumors are vital because they may be the sentinel presentation of familial adenomatous polyposis. If confirmed in larger studies, APC full gene sequencing and upper and lower gastrointestinal tract evaluation may need to be part of standard evaluation of patients with abdominal desmoid tumors.

Adenomatous Polyposis Coli↗
PubMed2004

Tumor suppressor APC blocks DNA polymerase beta-dependent strand displacement synthesis during long patch but not short patch base excision repair and increases sensitivity to methylmethane sulfonate.

In the present investigation, we report a previously unsuspected function of the tumor suppressor protein, APC (adenomatous polyposis coli), in the regulation of base excision repair (BER). We identified a proliferating cell nuclear antigen-interacting protein-like box sequence in APC that binds DNA polymerase beta and blocks DNA polymerase beta-mediated strand-displacement synthesis in long patch BER without affecting short patch BER. We further showed that the colon cancer cell line expressing the wild-type APC gene was more sensitive to a DNA-methylating agent due to decreased DNA repair by long patch BER than the cell line expressing the mutant APC gene lacking the proliferating cell nuclear antigen-interacting protein-like box. Experiments based on RNA interference showed that the wild-type APC gene expression is required for DNA methylation-induced sensitivity of colon cancer cells. Thus, APC may play a critical role in determining utilization of long versus short patch BER pathways and affect the susceptibility of colon cancer cells to carcinogenic and chemotherapeutic agents.

Adenomatous Polyposis Coli Protein↗
PubMed1998

Screening for APC mutations based on detection of truncated APC proteins.

Mutation of the adenomatous polyposis coli (APC) gene is frequently found in colorectal tumors from both familial adenomatous polyposis (FAP) and non-FAP patients. Analysis of APC mutation is time-consuming and costly due to the large size of the APC gene. As the majority of APC mutations result in the truncation of gene products, the detection of truncated APC proteins may be used as a screening method for APC mutations. The aim of this study is to establish a practical method of detecting truncated APC proteins for the screening of APC mutations. APC proteins in human colorectal cancer cell lines were analyzed by western blotting. Truncated APC proteins were expressed in all of the colorectal cancer cell lines studied. Two species of truncated APC proteins were expressed in two cell lines. Western blotting is a rapid, reliable screening method for APC mutations and provides information on both alleles.

Antibodies, Monoclonal↗
PubMed1999

Low prevalence of the APC I1307K sequence in Jewish and non-Jewish patients with inflammatory bowel disease.

A germline sequence alteration at codon 1307 of the APC gene (I1307K) has been reported in 6-7% of the Ashkenazi Jewish population in the United States. This alteration is believed to predispose the APC gene to a secondary mutation at the same locus, resulting in an increased risk of colorectal carcinoma. There is an increased risk of colorectal carcinoma in patients with inflammatory bowel disease (IBD), a relatively large proportion of whom are Ashkenazi Jews. We therefore sought to determine whether the I1307K sequence variant occurred in the germline DNA of IBD patients. To our surprise, we found this sequence in only two of 267 patients with IBD (0.7%), occurring in only 1.5% of Jewish IBD patients. The I1307K sequence variant was not found in 67 patients with esophageal cancer, 53 patients with gastric carcinoma (13 MSI-H and 44 MSI-negative), or ten patients with sporadic MSI-H colon cancer. These findings suggest that the I1307K sequence is relatively rare in the germline of Jewish as well as non-Jewish IBD patients. It does not appear to contribute to the increased colorectal cancer risk present in these patients.

Colorectal Neoplasms↗
PubMed1992

Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP).

To examine whether the dosage effect of germ-line mutations in patients with familial adenomatous polyposis (FAP) is sufficient to cause colorectal adenomas, or an additional somatic mutation of the normal allele is required as well, we have investigated somatic mutations of the APC gene in multiple adenomas developed in one FAP patient. In addition to a 5-bp deletion of one allele present constitutionally in this patient, the normal APC allele had been lost in five of seven DNA samples extracted from small adenomas (< 3 mm in diameter) with mild or moderate atypia. This result indicates that the inactivation of both alleles of the APC gene is probably essential for the development of an early-stage adenoma, in agreement with the two-hit mutational model underlying the concept of tumor suppressor genes.

Adenoma↗
PubMed1998

Dietary modulation of carcinoma development in a mouse model for human familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is caused by a dominant mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP progressively develop adenomas and carcinomas of the colon and rectum. We developed a mouse model for this disorder by genetically modifying the Apc gene. The resulting mice Apc1638 progressively develop neoplasms in the colon and remainder of the gastrointestinal tract. In this study when Apc1638 mice were fed a Western-style diet, they developed an increased incidence of the end point of carcinomas and number of invasive tumors. The findings therefore demonstrated dietary modulation of carcinoma incidence in mice with a targeted mutation providing a model for the study of gene-environment interactions in cancer.

Adenoma↗
PubMed2000

Eleven novel APC mutations identified in Portuguese FAP families.

Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant predisposition to colorectal cancer. In the present study we screened all of the exons of the APC gene in individuals belonging to 85 Portuguese FAP families. We here report eleven novel mutations which are predominantly frameshifts or single base substitutions, resulting in premature stop codons. Hum Mutat 16:178, 2000.

Adenomatous Polyposis Coli↗
PubMed2002

Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway.

Fibromatoses of the breast are nonmetastasizing tumors, but can be infiltrative and locally recurrent. Breast fibromatoses are rare, and their specific genetic alterations have not been elucidated. However, their occasional occurrence in patients with familial adenomatous polyposis (FAP) and their morphologic identification with other deep fibromatoses (desmoid tumors) suggest that alterations of the APC/beta-catenin pathway might be involved in the pathogenesis of sporadic and FAP-associated breast fibromatoses. We analyzed somatic beta-catenin and APC gene mutations in 33 breast fibromatoses (32 sporadic and 1 FAP-associated) using immunohistochemistry for beta-catenin, 5q allelic loss assays, and direct DNA sequencing for exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. Nuclear accumulation of beta-catenin was present in the stromal tumor cells in most (82%) cases but not in normal stroma or mammary epithelial cells. Somatic alterations of the APC/beta-catenin pathway were detected in 79% of breast fibromatoses, including activating beta-catenin gene mutations in 15 cases and somatic APC alterations (mutation or 5q allelic loss or both) in 11. These findings indicate that alterations of the APC/beta-catenin pathway with resultant nuclear translocation of beta-catenin are important in the pathogenesis of both sporadic and FAP-associated breast fibromatosis. The spectrum of beta-catenin and APC alterations is similar to that described for desmoid tumors of the abdomen, paraspinal region, and extremities.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Detection of mutations in the DNA polymerase delta gene of human sporadic colorectal cancers and colon cancer cell lines.

To test the hypothesis whether DNA polymerases acquire mutator properties during tumor development (mutator hypothesis), we examined DNA polymerase delta mRNA in 6 colon cancer cell lines (DLD-1, HCT116, SW48, HT29, SW480 and SW620) and 7 sporadic human colorectal cancers. For analysis we used amplification of cDNA by polymerase chain reaction, single-strand conformation polymorphism and sequencing techniques. In 5 of the cell lines, 9 mutations leading to changes of the amino acid sequence of DNA polymerase delta were detected. Most mutations were found in the cell lines DLD-1, HCT116 and SW48 for which defects in mismatch repair genes had been identified previously. In the majority of cases, wild type and mutated sequences were present. In 2 cell lines (HCT116 and SW48), a single-nucleotide deletion occurred at the same position. This resulted in a premature termination codon by which the DNA interaction domain of the enzyme was eliminated. Furthermore, sequence deviations were found in the tumor tissues of 4 colon cancer patients. Wild-type and altered sequences were present simultaneously. The deviations included missense mutations (2 cases) and silent mutations (2 cases). The missense mutations and one of the silent mutations were found in normal mucosa as well. In addition, the mutation clustered region of a tumor suppressor gene, often found to be defective in colon cancer, the adenomatous polyposis coli (APC) gene, was investigated in surgical specimens and cell lines. One carcinoma and 2 cell lines exhibited amino acid changes in both the DNA polymerase delta gene and in the mutation clustered region of the APC gene. Since most of the mutations detected in the DNA polymerase delta mRNA are likely to alter the structure of the protein, the enzyme is expected to be functionally impaired. In particular, copying fidelity might be decreased, thus contributing to the high mutation rate observed in colorectal cancer.

Aged↗
PubMed1996

Elevated cyclooxygenase-2 levels in Min mouse adenomas.

BACKGROUND & AIMS: Mutations in the APC gene result in an increased propensity to develop intestinal neoplasia; however, a complete understanding of the mechanisms resulting in tumor formation has remained elusive. Min mice possess a mutation in the APC gene and display a neoplastic phenotype similar to that observed in familial adenomatous polyposis coli in humans. Cyclooxygenase (COX) inhibitors decrease tumor multiplicity in the Min mouse intestine. The present study was designed to determine if there was an increase in COX-2 in adenomas harvested from Min mouse intestine. METHODS: COX-2 messenger RNA levels were determined by Northern blots and reverse-transcription polymerase chain reactions of B6Min x 129 mouse-derived tumors. Protein levels and localization were determined by Western blots and immunohistochemical staining. RESULTS: The Northern blots revealed an approximately threefold increase in the level of COX-2 messenger RNA in Min mouse adenoma compared with normal mucosa. COX-2 protein levels in adenomatous tissues were also approximately threefold higher compared with normal mucosa from the same mouse. Immunohistochemical staining with a monospecific COX-2 antibody confirmed that increases in COX-2 immunoreactivity were restricted to dysplastic and neoplastic foci within intestinal mucosa. CONCLUSIONS: These data show that COX-2 levels may be increased at an early stage in colorectal neoplasia during polyp formation and before invasion.

Adenoma↗
PubMed1994

[Familial adenomatous polyposis].

Familial adenomatous polyposis is a rare genetic disease with a dominant mode of inheritance, involved in 1% of colorectal cancer. The APC gene, responsible for the disease, has been localized on the long arm of chromosome 5 and has recently been cloned and sequenced. Mutations predicted to alter the coding property of the APC gene have been reported in large series of adenomatous polyposis patients. Some of them have been correlated with an attenuated phenotype. A genetic test has been developed in affected families. Systematic screening of registered at-risk relatives has allowed a significant reduction of the median age at adenomatous polyposis diagnosis, and thus the incidence of colorectal cancer.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Elevated serum triiodothyronine (t3) in Ashkenazi Jewish prostate cancer patients carrying the I1307k allele of the APC (adenopolyposis coli) gene.

PURPOSE: The risk of developing any cancer in carriers of the I1307K mutation of the adenopolyposis coli (APC) gene is significantly increased (odds ratio 1.5, P = 0.01). One of the cancers associated with the I1307K mutation is prostate cancer (odds ratio 2.0, P = 0.14). Also, there is an association of APC mutations with thyroid cancer. In this study, we measured triiodothyronine (t3) levels in Ashkenazi Jewish prostate cancer patients, with and without the I1307K mutation of the APC gene. MATERIALS AND METHODS: Participants in our study were found through urology and radiation oncology clinics in 1999 and 2000. All eligible patients were asked to take part. All patients had been initially diagnosed on the basis of rising PSA or abnormal physical examination. Histological confirmation of diagnosis was obtained for all subjects. Ethnic background was confirmed for all subjects by self-report or interview. The I1307K allele of the APC gene was detected by amplification of DNA isolated from peripheral blood according to standard polymerase chain reaction (PCR) and dot blot procedures. Serum t3 level was determined by fluorescent immunoassay with a standard, commercially available instrument. RESULTS: We studied 77 patients. The youngest patient was 46, the oldest 88, average age 67 +/- 7.2 (mean +/- SD). Eleven males carrying the APCI 1307K allele had significantly higher serum t3 levels than 66 males carrying the wild type allele. There were no homozygotes for the I1307K allele. None of the males had a t3 level that was above the normal range for our laboratory (137 ng/dl). CONCLUSIONS: Our findings of increased serum t3 level with the APC I1307K allele in prostate cancer patients is not surprising, given the mitogenic potential of t3. Further studies may clarify whether t3 elevation is the mechanism whereby APC gene mutations increase the risk of prostate cancer, or whether other pathophysiologic abnormalities are involved.

Aged↗
PubMed2000

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a dominantly inherited familial cancer syndrome characterized by an increased predisposition to colorectal cancer and other benign and malignant extra-colonic lesions. FAP has been linked to germline mutations of the adenomatous polyposis coli (APC) gene that encodes a protein with 2,843 amino acids that has important functions in the regulation of cell growth. A genotype-phenotype correlation has also been observed between mutations in the APC gene and polyp phenotype. We review the clinical and genetic features of this disorder and provide information on the diagnostic approaches and treatment options available for this disease.

Adenomatous Polyposis Coli↗
PubMed2006

Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature.

Mutations in the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP). Disease severity and the presence of extracolonic manifestations seem to be correlated with the location of the mutation on the APC gene. In this review, large studies describing genotype-phenotype correlations in FAP were evaluated and categorized. Attenuated FAP (AFAP, <100 colorectal adenomas) is correlated with mutations before codon 157, after codon 1595 and in the alternatively spliced region of exon 9. Severe polyposis (>1000 adenomas) is found in patients with mutations between codons 1250 and 1464. Mutations in the remainder of the APC gene cause an intermediate phenotype (hundred to thousands of adenomas). Congenital hypertrophy of the retinal pigment epithelium (CHRPE) and desmoid tumours are associated with mutations between codons 311 and 1444 and after codon 1444, respectively. No consistent correlations were found for upper gastrointestinal tumours. Genotype-phenotype correlations in FAP will be useful in decisions concerning screening and surgical management of FAP.

Adenomatous Polyposis Coli↗
PubMed2002

An insight into the genetic pathway of adenocarcinoma of the small intestine.

BACKGROUND: Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS: The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS: A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS: Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION: We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes.

Expression of anti-apoptotic genes is frequently elevated in tumors, where they increase resistance to chemotherapeutic agents and predict poor patient outcomes. However, key cellular factors regulating anti-apoptotic genes in tumors remain unknown. Increased expression of the regenerating (Reg) genes is commonly observed in gastrointestinal (GI) malignancies including colorectal cancer (CRC). We therefore examined Reg gene expression and associated changes in anti-apoptotic genes in an animal model of GI tumorigenesis. Using real time RT-PCR, we measured expression of Reg genes in human colorectal adenocarcinoma specimens, colon adenocarcinoma cell lines and adenomas from multiple intestinal neoplasia (min) mice heterozygous for a germ-line mutation of the adenomatous polyposis coli (APC) gene. Expression of Reg genes is increased in human colorectal adenocarcinomas and in the intestine of APCmin/+ mice at four weeks of age, a time preceding the spontaneous second mutation in the APC gene. Individual Reg genes exhibited regional expression profiles across the GI tract in mice. Adenomas from 14-week old mice had significant increases in at least one member of the Reg gene family, most commonly Reg IV and an associated increase in expression of the anti-apoptotic gene, Bcl-2. Addition of exogenous recombinant human Reg IV to human colon adenocarcinoma cells significantly increased Bcl-2 and Bcl-xL expression and induced resistance to ionizing radiation. These results show that dysregulation of Reg genes occur early in tumorigenesis. Furthermore, increased expression of Reg genes, specifically Reg IV contribute to adenoma formation and lead to increased resistance to apoptotic cell death in CRC.

Adenocarcinoma↗
PubMed2000

Asef, a link between the tumor suppressor APC and G-protein signaling.

The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. Here the APC gene product is shown to bind through its armadillo repeat domain to a Rac-specific guanine nucleotide exchange factor (GEF), termed Asef. Endogenous APC colocalized with Asef in mouse colon epithelial cells and neuronal cells. Furthermore, APC enhanced the GEF activity of Asef and stimulated Asef-mediated cell flattening, membrane ruffling, and lamellipodia formation in MDCK cells. These results suggest that the APC-Asef complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function.

Adenomatous Polyposis Coli Protein↗