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PubMed1998

Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in APC gene 1309 knockout mice.

The use of nonsteroidal anti-inflammatory drugs has been suggested to have a chemopreventive effect against colon carcinoma, through the inhibition of cyclooxygenases 1 and 2, in patients with familial adenomatous polyposis and in animal models. Acarbose, an alpha-glycosidase inhibitor, may also be chemopreventive. In order to examine the effects of these drugs we employed APC gene knockout mice randomized into 3 groups, one for treatment with piroxicam (0.05% concentration in drinking water), one for acarbose (0.04% concentration in food) and another for the control. After 14 weeks of treatment, mice were killed for quantitation of gastric and intestinal adenomas. Tumor multiplicity in the whole gastrointestinal tract decreased from 33.89 +/- 13.07 tumors/mouse in the control group to 17.05 +/- 7 tumors/mouse in the piroxicam-treated group (P < 0.001). The decrease in the acarbose-treated group (29.68 +/- 12.86 tumors/mouse) was not significant (P < 0.05). The number of tumors > or = 3 mm in diameter was also quantified in all gastrointestinal segments. The number of such tumors in the piroxicam group was decreased to 0.56 +/- 1.2 tumors/mouse from the control value of 3.78 +/- 1.17 tumors/mouse (P < 0.001), while in the acarbose-treated group the number decreased to 2.36 +/- 1.7 tumors/mouse (P < 0.01). Thus, piroxicam decreases the size and number of gastrointestinal adenomas in APC 1309 knockout mice, while acarbose decreases only the size.

Acarbose↗

PubMedDate not supplied

Enhanced expression of cyclooxygenase-2 and nuclear beta-catenin are related to mutations in the APC gene in human colorectal cancer.

Mutational inactivation of the human tumour suppressor gene adenomatous polyposis coli (APC) results in constitutive activation of beta-catenin/T cell factor-4 (Tcf-4) mediated transcription of target genes. Up-regulation of cyclooxygenase-2 (COX-2) protein is frequently found in human colorectal cancer (CRC). We analysed 38 CRC for mutations in APC and beta-catenin and found an association between APC mutations and elevated COX-2 levels. Furthermore, APC mutations were predominantly observed in tumour tissues from the rectum compared to tumours of colonic origin. Western blot analysis revealed that nuclear beta-catenin levels were generally higher in tumours with APC mutations compared to tumours with wild type APC. However, there was also a higher level of nuclear beta-catenin in tumour compared to normal tissue, but nuclear Tcf-4 protein was constitutively expressed in tumour and normal tissue and showed no differences. An identified putative Tcf-4 binding element in the COX-2 promoter may partly explain the enhanced level of COX-2 and support the idea that COX-2 may be a downstream target of the APC/beta-catenin/Tcf-4 pathway.

Adenocarcinoma↗

PubMed1992

Frequent somatic mutations of the APC gene in human pancreatic cancer.

The APC (adenomatous polyposis coli) gene is responsible for familial adenomatous polyposis and is also associated with the development of sporadic tumors of the colon and stomach. To investigate whether or not mutations of APC play any role in tumors arising in other organs, we examined somatic mutations of this gene in sporadic (nonfamilial) renal cell carcinomas, hepatocellular carcinomas, and cancers of the lung and pancreas. DNAs isolated from tumors were examined by means of a RNase protection analysis, coupled with the polymerase chain reaction followed by DNA sequencing of the polymerase chain reaction products. By screening a part of the APC coding region, we detected somatic mutations in four of ten pancreatic cancers; each of these mutations would yield a truncated APC product due to a 1- or 5-base pair deletion. These results imply that mutations in APC contribute to carcinogenesis in the pancreas.

Base Sequence↗

PubMed1999

Screening for mutations of the APC gene in 66 Italian familial adenomatous polyposis patients: evidence for phenotypic differences in cases with and without identified mutation.

Germline mutations in the APC gene are responsible for familial adenomatous polyposis (FAP), a dominantly inherited syndrome characterized by the development of hundreds to thousands of polyps in the colon and in the rectum of affected individuals and by variable extracolonic manifestations (gastric and duodenal polyps, osteomas, retinal lesions, and desmoid tumors). Through the combined use of single-strand conformation polymorphism (SSCP) analysis and the protein truncation test (PTT), we have screened 66 Italian FAP patients and found 29 different APC mutations in a total of 34 cases. Of the identified mutations, 15 were nonsense, 12 were 1- to 5-bp deletions or insertions and two were complex rearrangements, all leading to the formation of premature stop codons. Only 10 mutations had been already previously described at the germline level, confirming the high heterogeneity of the APC mutational spectrum. The mean age of diagnosis in mutation positive cases and their affected relatives was significantly lower than in cases without identified mutation (30.6 vs 39.1 years, respectively; p = 0.003). In addition, among patients without a family history of polyposis, all mutation-positive cases displayed at least one of the extracolonic manifestations usually associated with FAP, whereas in one-half of the cases without identified mutation, none of these phenotypes was observed. Although a fraction of apparently mutation-negative cases were likely to be due to limitations of the mutation screening strategy, our results suggest, in agreement with previous reports, that allelic and/or genetic heterogeneity might be responsible for the phenotypic variability observed in FAP patients.

Adenomatous Polyposis Coli↗

PubMed2002

Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma.

Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.

Adenocarcinoma↗

PubMed2003

The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations.

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited condition accounting for about 1% of all colorectal cancers, results from mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. The clinical spectrum and severity of FAP varies greatly with the mutation site, and both between and within families. Using the protein truncation test, single strand conformation polymorphism analysis and DNA sequencing, we identified 30 (75%) mutant alleles in 40 unrelated FAP families, for a total of 22 different APC mutations. Of these, 18 are known and 4 are novel: c.1797C>A (C599X), c.893_894delAC, (c.3225T>A; c.3226C>A) and c.4526_4527insT. Of the 30 APC gene mutations, 5 (approximately 17%) are nonsense mutations, 17 (approximately 57%) are small deletions, 5 (approximately 17%) are small insertions and 3 (approximately 10%) are complete deletions. All mutations occurred in single pedigrees, except those at codons 1061 and 1062, each found in two unrelated families, and the mutation at codon 1309 in exon 15, found in five unrelated families. About 40% of mutations, mostly small deletions and insertions, are located at repeated sequences; they promote misalignment-mediated errors in DNA replication and could represent a hot spot mutation region. This study enlarges the spectrum of APC gene mutations and sheds light on the correlation between the site of APC germline mutations and clinical manifestations of FAP.

Adenomatous Polyposis Coli↗

PubMed1999

Mutation analysis of the BRCA1 and BRCA2 genes results in the identification of novel and recurrent mutations in 6/16 flemish families with breast and/or ovarian cancer but not in 12 sporadic patients with early-onset disease. Mutations in brief no. 224. Online.

Since the identification of the BRCA1 and BRCA2 genes (MIM#s 113705 and 600185), more than hundred different mutations throughout both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. We analyzed 12 sporadic female patients with breast cancer before age 35, as well as 16 unrelated families, presenting with either (i) at least 3 first degree relatives with breast and/or ovarian cancer diagnosed at any age, or (ii) at least 2 first and/or second degree relatives with breast and/or ovarian cancer before age 45 years. We performed a protein truncation test for BRCA1 exon 11 and BRCA2 exons 10 and 11 and heteroduplex analysis for all the remaining exons of BRCA1 and 2. Presence of genomic deletions encompassing exons 13 or 22 of BRCA1, known to be Dutch founder mutations, was investigated by PCR. In 6/16 (37.5%) unrelated families the causal mutation in either the BRCA1 or BRCA2 gene was identified. Four different mutations were found in the BRCA1 gene: IVS5+3A>G (intron 5), 1191delC (exon 11), R1443X (exon 13), IVS22+5G>A (intron 22) and two in the BRCA2 gene: 6503delTT (exon 11), 6831delTG (exon 11). 1191delC (BRCA1) and 6831delTG (BRCA2) are novel mutations. IVS5+3A>G in exon 5 of BRCA1 published by Peelen et al. (1997) as a novel Belgian mutation, was identified in one additional family, not fulfilling our inclusion criteria. In the group of 12 sporadic female patients no mutations were found.

Adult↗

PubMed1997

Activation of adenomatous polyposis coli (APC) gene expression by the DNA-alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine requires p53.

Development of colon cancer is a multistep process frequently involving mutations in both the APC and p53 tumor suppressor genes. In this study we treated the HCT-116 colon cancer cell line with alkylating agents including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG),which is known to cause colon cancer in animals, and examined the expression of both APC and p53 genes. Exposure of cells with MNNG caused an 8-12-fold increase in the level of APC mRNA and protein. APC induction was shown to result from increased nuclear transcription of the APC gene and correlated with a concomitant increase in the p53 protein level after MNNG treatment. A necessary role for p53 in APC gene regulation is supported by the failure of MNNG to induce APC expression in cell lines either expressing very low levels of p53 (HeLa cells) or no p53 (K562 erythroleukemia cells). The overexpression of wild-type p53 gene into HCT-116 cells mimicked the effect of MNNG-induced expression of APC mRNA. A direct causal role for p53 in APC gene regulation was further evaluated by transfecting the wild-type p53 gene into K562 cells and observing a 5-fold increase in the APC gene expression. These results support a model featuring a direct link between p53 and APC in response to alkylation-induced DNA damage and suggest a novel role for p53 in a stress-response pathway involving APC.

Carcinogens↗

PubMed1992

Familial adenomatous polyposis: identification of a new frameshift mutation of the APC gene in an Italian family.

Familial Adenomatous Polyposis (FAP) is a premalignant disease of the gastrointestinal tract inherited as an autosomal dominant trait assigned to chromosome 5q21. The 15 exons of the APC gene responsible for the defect were amplified from the DNA of one FAP patient. SSCP analysis of the amplified DNA revealed a variant conformer of exon 10. The sequencing of the cloned PCR product showed a 1 base insertion at position 1370, creating a stop codon four nucleotides downstream. SSCP analysis of 20 family members and nucleotide sequencing of exon 10 in three affected members confirmed the Mendelian inheritance of the mutant allele.

Adenomatous Polyposis Coli↗

PubMed2006

Novel germline mutations in the APC gene of Cypriot patients with familial and sporadic adenomatous polyposis.

Familial adenomatous polyposis (FAP) is one of the two commonest familial syndromes that predispose to colorectal cancer. FAP is caused by mutations in the adenomatous polyposis coli (APC) tumour suppressor gene that has a high penetrance. The disease is characterized by the occurrence of hundreds to thousands of colorectal polyps, which if left untreated give rise to colorectal cancer. In Cyprus, there are no molecular data available as yet on families with FAP. This work presents the results of APC analysis in our population for the first time. The APC gene was analyzed in 33 DNA samples from 20 individuals belonging to four FAP families and 13 patients with sporadic polyposis. We identified three truncating mutations, four missense mutations and 11 polymorphisms. It is of interest that two of the three truncating mutations, 2307delA and Q1242X, are novel, which supports the existence of a unique genetic pool in the Cypriot population. This ethnic molecular study in addition to highlighting population heterogeneity also contributes to phenotype-genotype associations that are essential for the clinical management of FAP families in Cyprus.

Adenomatous Polyposis Coli↗

PubMed1992

Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.

Two yeast artificial chromosomes (YACs) spanning a total distance of 1.1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5' end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.

Adenomatous Polyposis Coli↗

PubMed2004

Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas.

Several lines of evidence show that the development of hepatocellular carcinoma (HCC) requires an accumulation of genetic alterations. However, molecular mechanism in HCC carcinogenesis remains unsolved. A total of 89 HCC samples were analyzed in this study to determine how alterations in the Wnt signaling pathway associate with the carcinogenesis of HCC. beta-catenin immunohistochemistry showed positive nuclear staining in 24 (27.0%) of the 89 HCC samples, indicating the existence of alterations in the Wnt signaling pathway in those 24 HCC samples. Mutations in the beta-catenin, Axin1 and Axin2 genes were detected in 10 (41.7%), 13 (54.2%) and 9 (37.5%) of the 24 beta-catenin-positive samples, respectively, but no mutation was detected in the APC gene. In conclusion, in addition to mutations in the beta-catenin gene, mutations in the Axin1 and Axin2 genes may alter the Wnt signaling pathway, resulting in accumulation of beta-catenin.

Adenomatous Polyposis Coli Protein↗

PubMed1996

Presymptomatic diagnosis of familial adenomatous polyposis using intragenic polymorphisms and CA repeats flanking the APC gene.

To assess the value of DNA markers for the diagnosis of familial adenomatous polyposis (FAP) in South Africa, two highly informative CA-repeat polymorphisms (LNS CA-repeat in D5S346 and YN5.64c CA-repeat in D5S82) flanking the adenomatous polyposis coli (APC) gene, and three intragenic restriction fragment length polymorphisms (RFLPs) (exon 11/RsaI, exon 15.11/MspI, 3'UTR/SspI), were used for haplotype analysis in 13 South African families with the disease. The combination of these polymorphic markers proved to be highly informative and allowed an accurate diagnosis of FAP in 34/35 of the at-risk individuals analysed. Indirect molecular screening can therefore provide a comprehensive pre-clinical diagnostic test for FAP in South Africa. No predominant haplotype was found to be associated with FAP within the South African population. This suggests the absence of founder-type mutations in affected families and therefore marker studies remain important for the pre-clinical diagnosis of FAP in South Africa.

Adenomatous Polyposis Coli↗

PubMed2000

Alterations of adenomatous polyposis Coli (APC) gene in oral squamous cell carcinoma.

The present study assessed the roles of Adenomatous Polyposis Coli (APC) tumor suppressor gene during oral carcinogenesis. Reduction of APC transcript levels and APC loss of heterozygosity (LOH) were found in 39% (7/18) and 29% (10/34) cases of oral squamous cell carcinoma (OSCC), respectively. The apparent APC heterozygosity (27%) in non-cancerous matched oral tissue (NCMOT) adjacent to OSCC at an exon 11 locus was significantly lower than normally found in the Taiwanese population (49%). These findings suggest that the allelic status of APC could indicate a cancer risk. No polymorphism of 11307 allele of APC was identified in NCMOT or OSCC. Our data indicated that alterations of APC are frequent molecular changes of OSCC. Advances in understanding of the APC alterations that accompany OSCC development might provide a means for early diagnosis and possibly new therapeutic strategies.

Carcinoma, Squamous Cell↗

PubMed1997

Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration.

Apc-associated intestinal tumor formation appears to require functional loss of both Apc alleles. Apc has, therefore, been classified as a tumor suppressor gene. Loss of APC protein function results in increased intracellular beta-catenin, a molecule important to both cell-cell adhesion and regulation of cellular growth. In mice bearing a germ-line Apc mutation, we found that enterocyte beta-catenin expression was also increased in histologically normal intestinal mucosa. Enterocyte crypt-villus migration was decreased by 25%, and treatment of Min/+ animals with sulindac sulfide normalized both beta-catenin expression and enterocyte migration. Our data suggest that alterations in enterocyte migration occur in cells bearing a single mutant Apc allele, and that sulindac sulfide may normalize enterocyte growth in these cells.

Analysis of Variance↗

PubMed2000

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia.

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

Adolescent↗

PubMed1993

Multiple forms of the APC gene transcripts and their tissue-specific expression.

We have detected multiple forms of RNA transcript from APC, the gene which is responsible for familial adenomatous polyposis (FAP). Transcriptional initiation occurs at three sites in two distinct non-translating exons at the 5' end of the gene. At least five different forms of 5' non-coding sequences, generated by alternative splicing, exist. The splicing mechanism seems to be regulated in a tissue-specific fashion, and one type of transcript contained an additional exon, which was transcribed specifically in brain. Analyses of mRNAs from two colorectal-tumor cell lines by reverse-transcriptase polymerase chain reaction (RT-PCR) revealed that one or another of the transcriptional forms was absent in both cell lines. This observation suggested the presence of mutations in the control region or the first exon of APC, or that mutation(s) could have affected the splicing efficiency or transcriptional initiation of the gene in these tumors. Furthermore, we found that the alternative splicing involving the 19 kDa protein of signal recognition particle (SRP19) gene, that is known to occur at exon 14 of APC, is also controlled in a tissue-specific manner, and one type of transcript lacked in some organs.

Adenomatous Polyposis Coli↗

PubMed2002

Genetic and epigenetic changes in the APC gene in sporadic colorectal carcinoma with synchronous adenoma.

BACKGROUND AND AIMS: Somatic APC mutation, frequently associated with colorectal tumors, is implicated in the early stage of tumorigenesis. This study was performed to identify APC-related colorectal tumorigenesis in sporadic colorectal carcinomas with synchronous adenoma. MATERIALS AND METHODS: We screened the entire coding region of APC and also assessed 5q LOH, 5q MSI, and promoter hypermethylation in fresh colorectal tissue and the lymphocytes of 31 patients with synchronous colorectal adenoma and carcinoma. RESULTS: The APC mutation prevalence was greater in carcinomas (70%) than in adenomas (45%). The 5q LOH and MSI were identified in 7 and in 5 of 31 carcinomas and in 6 each of 43 adenomas, respectively. The APC promoter methylation was identified in 3 cases each of both carcinomas and adenomas. Mutations in cases with 5q LOH were identified exclusively from codons 959 to the 3' end of exon 15. Otherwise mutations identified between exons 1 and 14 showed additional mutation on exon 15 and no additional mutation in two cases. All carcinomas with 5q LOH, 5q MSI, or methylation included at least one APC mutation, whereas 5 carcinomas and 6 adenomas showed solely an APC mutation. Both alleles were disrupted in 1 of 31 normal mucosa (3.2%), 12 of 40 adenomas (30%), and 18 of 33 carcinomas (54.5%). CONCLUSION: Genetic and epigenetic events encompassing APC occur variously among patients and tissues in sporadic colorectal cancer patients with synchronous colorectal adenoma. Moreover, these changes sometimes appear to be accumulated in all of the stages of colorectal tumorigenesis.

Adenoma↗