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PubMed1998

The APCI1307K allele and cancer risk in a community-based study of Ashkenazi Jews.

Mutations in APC are classically associated with familial adenomatous polyposis (FAP), a highly penetrant autosomal dominant disorder characterized by multiple intestinal polyps and, without surgical intervention, the development of colorectal cancer (CRC). APC is a tumour-suppressor gene, and somatic loss occurs in tumours. The germline T-to-A transversion responsible for the APC I1307K allele converts the wild-type sequence to a homopolymer tract (A8) that is genetically unstable and prone to somatic mutation. The I1307K allele was found in 6.1% of unselected Ashkenazi Jews and higher proportions of Ashkenazim with family or personal histories of CRC (ref. 2). To evaluate the role of I1307K in cancer, we genotyped 5,081 Ashkenazi volunteers in a community survey. Risk of developing colorectal, breast and other cancers were compared between genotyped I1307K carriers and non-carriers and their first-degree relatives.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Restorative proctocolectomy: operative safety and functional outcomes.

Restorative proctocolectomy (total proctocolectomy and ileal J pouch anal anastomosis) has been accepted as the operation of choice in the setting of chronic ulcerative colitis and familial adenomatous polyposis. The purpose of this study was to assess operative safety and functional outcome after restorative proctocolectomy. A total of sixteen patients underwent surgery between January 1996 and December 1999. Hand sewn anastomosis with diverting ileostomy was performed in 9 patients and double stapled anastomosis in 7 patients. The underlying disease was ulcerative colitis in 9 cases and familial adenomatous polyposis in 7. Postoperative complications developed in 8 cases (50%), and intestinal obstruction was found in 4 cases (2 cases were operated upon). Anastomosis related complications were stenosis (n=2), leak (n=1) and perianal abscess (n=1). All patients were followed up at the outpatient clinic using questionnaires, with a mean follow up period of 19.9 months. The frequency of bowel movement was 8.2 per day in hand sewn anastomosis (HS), and 12 per day in double stapled anastomosis (DS) 3 months after surgery (period 1). This frequency decreased to 5.5 per day in HS, and 4.6 per day in DS after one year (period 2). Day and night continence was shown in 12/15, and 5/15, respectively in period 1, but improved to 10/11, and 10/11, respectively in period 2. Night time incontinence was noted in 10 of 15 patients in period 1 (seepage 3/15, soiling 7/15). The need to take anti-diarrheal medication, and to use a pad was noted in 2/15, and 10/15, respectively in period 1, but no patient took antidiarrheal medication or wore a protective pad in period 2. Postoperative urinary function was satisfactory in 13/14 patients. Postoperative sexual function was analyzed in a total of 8 patients, who showed good erection (5/5), ejaculation (5/5) and satisfactory sexual life (5/5). In females, 3 patients showed a satisfactory sexual life. In conclusion, restorative proctocolectomy for chronic ulcerative colitis and familial adenomatous polyposis can be performed safely with excellent functional outcomes, including bowel movement, urinary and sexual functions one year after surgery.

Adenomatous Polyposis Coli↗
PubMed2005

A comprehensive strategy to combat colon cancer targeting the adenomatous polyposis coli tumor suppressor gene.

Somatic cells in the majority of colorectal polyps and cancers contain mutations/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. APC is involved in normal intestinal development and acts to influence a variety of cellular processes. Loss of APC function leads to intestinal neoplasia in both mice and humans. APC influences expression of specific genes, including the c-Myc oncogene, which functions as a transcriptional activator. Loss of APC function leads to alterations in c-Myc-regulated genes including ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. A single nucleotide polymorphism (SNP) in the ODC promoter affecting c-Myc-dependent expression has been associated with risk of colorectal and other cancers. Pharmaceuticals that target structural features of the c-Myc promoter, and suppress expression of c-Myc and other genes regulated by similar promoter elements, are being developed as potential colorectal cancer chemotherapies. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, is under clinical evaluation as a colorectal cancer chemopreventive agent. APC and APC-dependent genes, such as c-Myc and ODC, may be useful as genetic markers of risk and as targets for chemoprevention and therapy for colorectal cancer.

Adenomatous Polyposis Coli Protein↗
PubMed2003

Hereditary polyposis syndromes and hereditary non-polyposis colorectal cancer.

Colorectal cancer due to hereditary syndromes comprises approximately 5% of the overall colorectal cancer burden. Conditions fall into two distinct categories, the polyposis syndromes and hereditary non-polyposis colorectal cancer. It is important for the clinician to have a working knowledge of both as screening and surveillance recommendations differ significantly from those applicable to the general population. The polyposis syndromes include familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. For each condition, a review of both the intestinal and extra-intestinal clinical findings is presented as well as the genetic basis, genetic testing, screening, surveillance and treatment options. As genetic testing for several of these conditions has recently become both commercially available and standard practice, special attention is given to indications and strategies for genetic testing in hereditary colorectal cancer syndromes.

Adenomatous Polyposis Coli↗
PubMed1987

Expression of carcinoembryonic antigen, T-antigen, and oncogene products as markers of neoplastic and preneoplastic colonic mucosa.

Several crypt abnormalities have been demonstrated in the mucosa of neoplastic and preneoplastic lesions of the large intestine. In addition, certain tumor markers are expressed in large intestinal carcinoma but not in normal mucosa. To determine whether any correlation exists between tumor marker expression and crypt abnormalities and at what stage markers are expressed, we studied specimens of large intestinal mucosa from 13 patients with preneoplastic conditions (adenomatous polyp, familial polyposis, Crohn's disease, and ulcerative colitis). The tumor markers examined include carcinoembryonic antigen (CEA), the ras gene products p21 and p21ser (mutated form), and beta-D-galactosyl-(1----3)-alpha-N-acetyl-D-galactosamine (gal--gal NAc, also known as T-antigen). Results were compared to those of five cases of adenocarcinoma of colon and three control cases of colonic mucosa obtained at immediate autopsy. All four markers were expressed in three of the five cases of adenocarcinoma, but none were expressed in the control cases. Variable expression of each marker was demonstrated in the dilated, distorted crypts of preneoplastic lesions. CEA and gal--gal NAc appeared to be expressed most frequently, suggesting that these are common markers or are expressed at an earlier stage in the neoplastic process than p21 or p21ser. Demonstration of such markers in preneoplastic conditions may be of use in determining the malignant potential and in monitoring these lesions.

Antigens, Neoplasm↗
PubMed2006

Effect of cyanidin-3-glucoside and an anthocyanin mixture from bilberry on adenoma development in the ApcMin mouse model of intestinal carcinogenesis--relationship with tissue anthocyanin levels.

Anthocyanins are dietary flavonoids, which can prevent carcinogen-induced colorectal cancer in rats. Here, the hypotheses were tested that Mirtoselect, an anthocyanin mixture from bilberry, or isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, interfere with intestinal adenoma formation in the Apc(Min) mouse, a genetic model of human familial adenomatous polyposis, and that consumption of C3G or Mirtoselect generates measurable levels of anthocyanins in the murine biophase. Apc(Min) mice ingested C3G or Mirtoselect at 0.03, 0.1 or 0.3% in the diet for 12 weeks, and intestinal adenomas were counted. Plasma, urine and intestinal mucosa were analyzed for presence of anthocyanins by high-pressure liquid chromatography with detection by UV spectrophotometry (520 nm) or tandem mass spectrometry (multiple reaction monitoring). Ingestion of either C3G or Mirtoselect reduced adenoma load dose-dependently. At the highest doses of C3G and Mirtoselect adenoma numbers were decreased by 45% (p < 0.001) or 30% (p < 0.05), respectively, compared to controls. Anthocyanins were found at the analytical detection limit in the plasma and at quantifiable levels in the intestinal mucosa and urine. Anthocyanin glucuronide and methyl metabolites were identified in intestine and urine. Total anthocyanin levels in mice on C3G or Mirtoselect were 43 ng and 8.1 microg/g tissue, respectively, in the intestinal mucosa, and 7.2 and 12.3 microg/ml in the urine. The efficacy of C3G and Mirtoselect in the Apc(Min) mouse renders the further development of anthocyanins as potential human colorectal cancer chemopreventive agents worthwhile.

Adenoma↗
PubMed1997

Quantitation of in vivo gene delivery by restriction enzyme PCR generated polymorphism.

The Multiple intestinal neoplasia (Min) mouse develops multiple polyps in the intestine, due to a heterozygous mutation of the Apc locus. Our laboratory has been introducing normal human adenomatous polyposis coli (APC) gene into the Min mouse through liposome enema to prevent or reverse polyp formation. We have quantitated the amount of normal human APC gene delivered in vivo by a restriction enzyme site specific quantitative PCR. Adult Min and BALB/C mice were treated with lipofectant and human APC complementary DNA (cDNA) plasmid. Min colonic DNA was amplified using primers for Apc nucleotide 2524F (5'2524-TCTCGTTCTGAGAAAGACAGAAGCT) and 2679R (5"2679-TGATACTTCTTCCAAAGCTTTGGCTAT). Highlighted primer sequences were purposely different so as to generate two HindIII restriction enzyme sites in the presence of normal mouse Apc (Apc+). Genomic DNA from untreated Min colonic epithelium revealed two bands: 144 bp for ApcMin and 123 bp for Apc+. BALB/C DNA was amplified using primers flanking a region within the APC gene containing a HindIII site on the human APC, which is absent in the murine APC (Apc). Min's DNA extracted 24 hr after treatment demonstrated a plasmid content of 3% due to a relative increase in the Apc+ (123 bp) band. Six weeks of treatments increased delivery to 10%. APC gene therapy of colonic epithelium can be quantitatively measured through restriction enzyme quantitative PCR. Long-term treatment further increases gene delivery. PCR generated polymorphism is a reliable and reproducible technique to initially optimize transfection conditions and ultimately quantitate efficacy in an in vivo gene delivery model.

Adenomatous Polyposis Coli↗
PubMed2000

Suppression of polypogenesis in a new mouse strain with a truncated Apc(Delta474) by a novel COX-2 inhibitor, JTE-522.

Mutations of the adenomatous polyposis coli gene (Apc) have been implicated in the occurrence of sporadic colon cancer. Various Apc knockout strains of mice have been created to better understand the function of this gene. In the present study, using gene targeting, we disrupted the mouse Apc gene at the end of exon 10 to compare its effect with the effects of other types of Apc gene disruption, all of which are on exon 15. The mice expressed a mutant form of mRNA that encoded 474 amino acids instead of 2845 amino acids due to exon duplication. In addition, these Apc(Delta474) knockout mice developed intestinal and mammary tumors. Since the most severe cases of familial adenomatous polyposis are associated with mutations on exon 15, our mutation at exon 10 was expected to result in a mild phenotype. However, the number of polyps that our mice developed was similar to that of other Apc knockout mice such as Apc(Min) and Apc(1309) mice. Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinoma. Apc(Delta474) mice treated with JTE-522, a novel COX-2-selective inhibitor, showed a significantly reduced number of polyps. These results suggest that COX-2 plays an important role in polypogenesis and COX-2-selective inhibitors can be used as new preventive therapeutics against colorectal tumors.

Adenomatous Polyposis Coli↗
PubMed2003

Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.

Gastric adenomas are unusual neoplasms that can constitute one of the direct precursors to gastric adenocarcinoma. Most gastric adenomas are comprised of polypoid projections of dysplastic epithelium with at least focal intestinal-type differentiation (containing goblet cells and/or Paneth cells), whereas adenomas comprised entirely of dysplastic foveolar-type epithelium are rare. It has been shown that nearly all intestinal-type adenomas arise in association with background intestinal metaplasia and gastric atrophy, approximately 40% harbor high-grade dysplasia, and nearly one fourth progress to adenocarcinoma. In contrast, foveolar-type adenomas tend to occur in otherwise normal, nonatrophic gastric mucosa and rarely harbor high-grade dysplasia or carcinoma. Potential differences in the genetic alterations between intestinal-type and foveolar-type gastric adenomas have not been systematically studied. We investigated 11 intestinal-type and 7 foveolar-type gastric adenomas (all from patients without familial adenomatous polyposis) for alterations in APC (using 5q allelic loss assays and direct DNA sequencing of the mutation cluster region), beta-catenin (using direct DNA sequencing of the phosphorylation region in exon 3), K-ras (using direct DNA sequencing of codons 12 and 13), and microsatellite instability (MSI; using fluorescent-based PCR amplification of a standard panel of 5 microsatellite markers). Overall, 10 of 11 (91%) intestinal-type adenomas harbored at least one detectable genetic alteration, whereas only 3 of 7 (43%) of foveolar-type adenomas did (P =.047). However, no statistically significant differences in any particular genetic alteration were found. Among intestinal-type adenomas, APC alterations were present in seven (64%), high-level MSI in three (27%), and K-ras mutations in two (18%). Among foveolar-type adenomas, APC alterations were present in three (43%) and a K-ras mutation in one of six amplifiable polyps (17%). Neither APC nor MSI correlated with the size of the adenoma, but K-ras mutations were found only in lesions of > or = 1 cm. beta-catenin mutations were not present in any gastric adenoma, irrespective of the presence or absence of APC alterations. These results suggest that the types and frequencies of genetic alterations occurring in gastric and colorectal adenomas are similar. Although intestinal-type and foveolar-type gastric adenomas display divergent biologic behavior, the specific genetic events accounting for these differences in morphology and biologic behavior are unclear.

Adenoma↗