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PubMed1996

Mutation detection in exons 1-14 of the adenomatous polyposis coli gene: identification of an alternatively spliced transcript.

Mutations in the APC gene are responsible for the dominantly inherited colon cancer syndrome, familial adenomatous polyposis (FAP). We have designed PCR primers which allow amplification by RT-PCR of exons 1-14 of the APC gene in six overlapping segments. The amplicons have been screened for the presence of mutations in patients affected with FAP using heteroduplex analysis. One patient has been identified with an alternatively spliced transcript involving exon 14 and a single base insertion mutation within the same exon.

Alternative Splicing↗
PubMed2002

Preclinical studies of gene transfer for the treatment of desmoid disease in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) arises following mutation or loss of the adenomatous polyposis coli (APC) gene. Desmoid tumours are proliferations of fibroblasts and occur as an extracolonic manifestation of FAP. They are a leading cause of death after colectomy. The aim of this study was to assess the potential for APC gene transfer into fibroblasts in vitro and in vivo as a basis for consideration of gene therapy in the prevention or treatment of desmoid tumours. METHODS: The APC gene was transferred by lipofection into fibroblasts in tissue culture and into peritoneum and small bowel mesentery in vivo. Reverse transcriptase-polymerase chain reaction was used to determine whether or not transfection was successful. RESULTS: Transgene expression was recorded in vitro to 7 days after transfection. High levels of transgene expression were also seen in samples of peritoneum (all eight mice), small bowel mesentery (seven of eight), liver (seven of eight) and intestinal tissues (five to six of eight) following intraperitoneal treatment. Interestingly, transgene expression in gonadal tissues was occasionally noted. CONCLUSION: Liposomal transfection of APC gave prolonged high-level expression of the transgene, an important basis for gene therapy. No adverse effects were recorded. Further work is needed in animal models of desmoid disease to assess the clinical effects of gene therapy.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

[Etiology of colorectal cancer].

Colorectal cancer affect the 15% of general population in developed countries. Cancer is a multistep process in which multiple genetic alterations must usually occur in several years. The premalignant step consists of one or multiple aberrant crypts due to hyperproliferation of cells and its shift from the deep third of the crypt to its surface. It has been suggested that abnormality in the APC gene is responsible for this. Furthermore, there exists DNA hypometilation, activation of the gene K-ras and ornithine decarboxylase activity. There is also a loss of MCC gene, that seems to interact with the APC gene. Entire alterations described make possible the Class I adenoma formation. This adenoma, needs the loss of the DCC gene (late stage in the carcinogenesis process), to become a Class II adenoma. The following alteration is deleted and mutation of the p53 gene. There is also an activation of the c-myc oncogene. These two genes are important mechanisms for the conversion of a benign adenoma to a malignant one, adenoma with in situ carcinoma or Class III adenoma. This type of adenoma becomes carcinoma and metastatic stage, throughout inactivation of several tumor suppressor genes. Besides the hereditary APC alteration and other acquired genetic changes as described above there are other associated genetics, antigenics, and enzymes that have an important role in the adenoma-carcinoma sequence. Several carcinogenic factors have been described which also contribute in the adenoma and carcinoma formation: ulcerative colitis, acromegaly, familial history of colonic neoplasia, certain professions, smoking and drinking, consumption of red or processed meat, etc.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed2000

Cortisol producing adrenal adenoma--a new manifestation of Gardner's syndrome.

INTRODUCTION: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. Gardner's syndrome is a variant of FAP in which desmoid tumors, osteomas and pigmented retinal lesions occur together with intestinal manifestations. The APC gene (adenomatous polyposis coli) at 5q21 is a tumor suppressor gene which is mutant in FAP. PATIENT: A 36 year old woman presented with a history of polyposis ventriculi, ovarian desmoid cysts, and disseminated desmoid tumors. Her familial history was unremarkable. On admission she complained weight gain, secondary amenorrhea, and episodes of hypertension followed by paroxysmal headache. RESULTS: Elevated urinary free cortisol (878 microg/24h), suppressed basal ACTH (< 5 pg/ml) and insuppressible serum cortisol after low dose dexamethasone (189 ng/ml) revealed adrenal Cushing's syndrome. Abdominal NMR showed an adrenal mass two centimeter in diameter with inhomogeneous contrast enhancement. Unilateral adrenalectomy was performed and an adrenal adenoma was diagnosed by histological criteria. For mutational detection DNA from peripheral blood leucocytes was extracted. A protein truncation test was performed, which revealed a termination mutation between codon 1099 and 1623 of the APC gene. Direct sequencing showed a point mutation in exon 15 of the APC gene at position 1542 (CAG --> TAG). This region is known to be altered in patients with extraintestinal manifestation of FAP. CONCLUSION: In patients with Gardner's syndrome adrenal tumors leading to hormonal excess should be considered. Whether mutations in the APC gene have implications in sporadic adrenal tumorigenesis needs to be proven.

Adenoma↗
PubMed1994

Loss of heterozygosity affecting the APC and MCC genetic loci in patients with primary breast carcinomas.

Tumor suppressor genes APC and MCC were identified recently, and their chromosomal location was ascribed to chromosome 5q21. Mutations in the APC gene give rise to familial adenomatous polyposis and occur in many perhaps even the majority, of sporadic colon cancers. Loss of heterozygosity has been described in other human tumors such as lung and esophageal cancers. Here we show loss of heterozygosity (LOH) in 87 patients with breast cancer for the APC and/or MCC loci using a polymerase chain reaction-LOH assay. LOH affected loci in APC exons 11 and 15 in 9 of 35 (25%) and 4 of 34 (11%) heterozygous patients, respectively. LOH at the MCC exon 10 locus occurred in 7 of 40 (17%) informative samples. These data suggest that allelic deletion of APC and/or MCC is probably involved in the pathogenesis and/or progression of a subset of breast cancers.

Base Sequence↗
PubMed1995

APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis.

Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). Genotype-phenotype correlation studies in patients with FAP have demonstrated associations of certain variants of the disease with mutations at specific sites within the APC gene. In a large FAP family, we identified a frameshift mutation located in the alternatively spliced region of exon 9. Phenotypic studies of affected family members showed that the clinical course of FAP was delayed, with gastrointestinal symptoms and death from colorectal carcinoma occurring on average 25 and 20 years later than usual, respectively. The numbers of colorectal adenomas differed markedly among affected individuals and the location of colorectal cancer lay frequently in the proximal colon. Our findings suggest that the exon 9 mutation identified in the pedigree is associated with late onset of FAP. The atypical phenotype may be explained by the site of the mutation in the APC gene. Analysis of the APC protein product indicated that the exon 9 mutation did not result in a detectable truncated APC protein. Given the location of the mutation within an alternatively spliced exon of APC, it is conceivable that normal APC proteins are produced from the mutant allele by alternative splicing.

Adenoma↗
PubMed1994

Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis.

In the course of presymptomatic diagnosis in families with familial adenomatous polyposis (FAP) we screened 202 unrelated patients for mutations in the APC gene. Germ-line mutations were identified in 20.8% of the index patients by a single step screening procedure based on heteroduplex analysis of a PCR product encompassing codons 1027-1384 of the APC gene. The most common mutations in our sample were a 5 bp deletion at codon 1309 in 9% of the families, a 5 bp deletion at codon 1061 in 5% and a 4 bp deletion at codon 1068 in 2.5% of the families. In addition, 11 novel mutations localized within the exons 11-15 of the APC gene were identified by the heteroduplex or SSCP methods.

Adenomatous Polyposis Coli↗
PubMed2002

Microadenomatous lesions involving loss of Apc heterozygosity in the colon of adult Apc(Min/+) mice.

Mutations in the human adenomatous polyposis coli (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. Mouse model for human FAP, Apc(Min/+) mouse, contains a truncating mutation in the Apc gene and spontaneously develops intestinal adenomas. However, the distribution of tumors along the intestine found in Apc(Min/+) mice is different from that in human FAP. A majority of intestinal polyps in the Apc(Min/+) mice is known to be located in the small intestine but rarely detected in the colon. We report here that adult Apc(Min/+) mice develop dozens of microadenomatous lesions in the colon (>20 lesions/colon). Surprisingly, the vast majority of such adenomatous lesions consisting of colonic crypts were <300 microm in their greatest dimension, whereas lesions in the small intestine showed various sizes. The allelic loss analysis revealed that these adenomatous crypts in the colon have already lost the remaining allele of Apc. Such findings suggest that, in contrast to tumorigenesis in the small intestine, loss of heterozygosity of the Apc gene is not sufficient for tumor development in the colon of Apc(Min/+) mice. Our results may give an account for the low incidence of colonic tumors in Apc(Min/+) mice.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Molecular biology of colon polyps and colon cancer.

From a histologic and endoscopic standpoint, colon and rectal cancer (CRC) begins as a small neoplastic polyp which progressively enlarges and transforms through a dysplasia stage into invasive cancer. Recently, molecular abnormalities underlying the adenomacarcinoma progression have been defined. The adenomatous polyposis coli (APC) gene and mismatch repair genes are found to be dysfunctional early in the neoplastic process; either as inherited or somatic mutations. Subsequently, polyps progress to cancer along one of two paths depending on which gene is abnormal. When the APC gene is the initial mutation tumor development follows the "loss of heterozygocity" (LOH) pathway. If mismatch repair genes are altered, the "replication error" (RER) pathway is followed. Somatic mutations of the K-ras oncogene and the MCC, DCC, and p53 tumor suppressor genes accumulate in the LOH pathway and mark the progression through polyp stages. Microsatellite instability is a characteristic of the RER pathway but the precise genes involved in this pathway currently are not known. Defining these pathways has led to a new classification scheme for CRC with resultant changes in our clinical approach to screening, surveillance, and treatment.

Adenomatous Polyposis Coli↗
PubMed1993

Molecular diagnosis of familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis is an inherited disease characterized by multiple colorectal tumors. The diagnosis has classically been based on the detection of multiple colorectal adenomas. The recent identification of germline mutations of the APC gene in patients with familial adenomatous polyposis makes presymptomatic molecular diagnosis possible, but the widespread distribution of the many mutations within this very large gene have heretofore made the search for such mutations impractical. We describe a novel approach that allows molecular genetic diagnosis in the majority of patients with the disease. METHODS: We screened 62 unrelated patients from the Johns Hopkins Familial Adenomatous Polyposis Registry for germline APC mutations. Primary screening was accomplished by analysis of protein synthesized in vitro from surrogate APC genes. In addition, the relative amount of transcript from each APC allele was determined with an allele-specific--expression assay. RESULTS: The protein assay revealed truncated protein in 51 of the 62 patients (82 percent). In 3 of the 11 remaining patients, the allele-specific--expression assay revealed significantly reduced expression of one allele of the APC gene. The use of these two assays in combination successfully identified germline APC mutations in 87 percent of the 62 patients. CONCLUSIONS: The protein and allele-specific--expression assays provide a practical and sensitive method for molecular diagnosis of familial adenomatous polyposis. This approach will facilitate care, allowing routine testing of subjects at risk and genetic confirmation of spontaneous mutations.

Adenomatous Polyposis Coli↗
PubMed2004

Ki-ras gene mutations, LOH of the APC and DCC genes, and microsatellite instability in primary colorectal carcinoma are not associated with micrometastases in pericolonic lymph nodes or with patients' survival.

AIMS: The primary aim of this study was to look for possible correlations between molecular genetic changes in primary colorectal cancer and the presence or absence of micrometastases in the accompanying pericolonic lymph nodes. The secondary aim was to correlate the data on these molecular genetic changes and micrometastases with survival. METHODS: One hundred and twenty five Dukes's stage B colorectal cancers from 1989 to 1992 were analysed. The primary tumours were evaluated for Ki-ras mutation, adenomatous polyposis coli (APC) loss of heterozygosity (LOH), deleted in colon cancer (DCC) LOH, and microsatellite instability using standard molecular techniques. All available lymph nodes were immunohistochemically stained for micrometastases. RESULTS: Micrometastases were present in 41% of patients. There were significantly more lymph nodes removed in the patients with micrometastases. Micrometastases were not associated with Ki-ras mutation, APC LOH, DCC LOH, or microsatellite instability, even when controlling for the number of lymph nodes removed. None of the molecular variables considered had a significant impact on either overall survival or on death with disease. CONCLUSIONS: There are insufficient data to justify using molecular genetic changes in primary colorectal carcinomas as prognostic markers. Micrometastases do not provide prognostic information on survival. There is value in increasing the numbers of lymph nodes removed and analysed along with the primary tumour.

Aged↗
PubMed2002

Impact of Helicobacter pylori infection and mucosal atrophy on gastric lesions in patients with familial adenomatous polyposis.

BACKGROUND AND AIMS: The role of Helicobacter pylori and atrophic gastritis in the pathogenesis of gastric lesions in familial adenomatous polyposis (FAP) has not been clarified. PATIENTS: Thirty one patients with FAP. METHODS: The presence of fundic gland polyposis (FGP) and gastric adenoma (GA) was determined by upper endoscopy with biopsies. The degree of gastric mucosal atrophy and H pylori status were determined by serological and histological findings. Germline mutation in the adenomatous polyposis coli (APC) gene was determined by polymerase chain reaction based single strand conformation polymorphism and direct sequencing. RESULTS: Gastric lesions were detected in 23 patients (74%). FGP and GA were found in 52% and 39%, respectively. APC gene mutation was identified in 22 of 30 patients. Patients with FGP were less frequently infected with H pylori than those without FGP (13% v 67%). The former patients had a lower degree of atrophy than the latter. Patients with GA tended to be more frequently infected with H pylori and they had higher degrees of atrophy than those without GA. When subjects were subdivided by gastric lesions (FGP alone, FGP+GA, GA alone, and negative groups), the GA alone group had the lowest pepsinogen I/II ratio and the highest seropositivity for H pylori. GA was found more frequently in patients positive for the APC mutation whereas no such a trend was observed in FGP. CONCLUSIONS: In FAP, H pylori associated atrophic gastritis contributes negatively to FGP. It seems to contribute positively to GA, especially in patients with truncating APC gene mutation.

Adenoma↗
PubMed2005

Novel adenomatous polyposis coli gene promoter is located 40 kb upstream of the initiating methionine.

The product of the oncosuppressor adenomatous polyposis coli (APC) gene is involved in cell cycle arrest and apoptosis and its loss of function is associated with the development of colorectal carcinogenesis. Its transcriptional regulation seems rather complex and has not been completely elucidated up to now. In an attempt to identify the transcription start sites for the mouse Apc gene we have detected a novel transcript in mouse embryonic stem (ES) cells and colon tissue. This transcript contains an untranslated exon, whose flanking sequences exhibited strong promoter activity in transient transfection experiments. These results suggest that we have identified a novel promoter for the mouse Apc gene, localized about 40 kb upstream of the initiating methionine, which drives expression of the unique Apc transcript type detected in undifferentiated totipotent ES cells. Transcripts bearing the novel exon combined either with exon 1 or with exon 2 were detected in all mouse tissues tested.

3' Flanking Region↗
PubMed1995

Genetic counselling and gene mutation analysis in familial adenomatous polyposis in Western Australia.

OBJECTIVE: To assess the provision of accurate pre-symptomatic genetic testing with DNA analysis and appropriate counselling for individuals and families known to be at high risk of developing familial adenomatous polyposis coli (FAP). PATIENTS AND METHODS: Thirty-one families with clinically and pathologically documented FAP were ascertained from the Western Australian Polyposis Registry. DNA was collected from over 200 individuals in these families to establish their genetic risk status for FAP, either by direct mutation analysis, or by linkage analysis. Individuals undergoing DNA testing were given intensive psychosocial support and counselling. RESULTS: In 19 families DNA-based counselling could not be offered because either the adenomatous polyposis coli (APC) gene mutation could not be detected or there were insufficient family members for linkage analysis. Gene testing yielded mutations of the APC gene in 87 individuals from 12 families; by gene tracking (or linkage analysis) in three families and by mutation analysis in the remaining nine (four of which had only one affected individual). DNA results conformed with a definite clinicopathological diagnosis in 27 FAP patients and, of the remaining 60 high-risk subjects tested, 14 had inherited the mutated APC gene. CONCLUSIONS: DNA analysis allowed accurate genetic counselling for 12 of 31 families affected by FAP, thus improving the medical and personal management in asymptomatic people who would otherwise be subjected to the uncertainty of long term surveillance and repeated colonic examinations. In future a superior biomolecular approach to gene mutation analysis, such as the protein truncation test, will facilitate management for most FAP individuals and families.

Adenomatous Polyposis Coli↗
PubMed2006

Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas.

To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINT1, MINT2, MINT31, MLH-1, MGMT, p14, p16, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel.

Aged↗
PubMed2001

Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene.

Papillary thyroid carcinoma (PTC) is a rare extracolonic manifestation of familial adenomatous polyposis, determined by germline mutations of the adenomatous polyposis coli (APC) gene. The aim of this study was to assess the presence of loss of heterozygosity of APC in the thyroid tumoral tissue. Specimens from six female patients, aged 20-36, were analyzed for germline and somatic mutations of the APC gene by restriction enzyme analysis and sequence analysis. Five of the six also had analysis for ret/PTC, a chimeric gene, the activation of which is restricted to papillary TC. Because a previous study showed that germline mutations in familial adenomatous polyposis-associated thyroid carcinoma were located between codons 140 and 1513, the search for somatic mutations of the APC gene was restricted to this genomic area. Three of the six patients, belonging to the same kindred, had a germline mutation at codon 1061. The remaining three, one per kindred, had germline mutations at codons 1061, 1061, and 1309, respectively. None of the six patients had loss of heterozygosity for APC or somatic mutation in the explored genomic area (codon 545 and codons 1061-1678). Four of five had activation of ret/PTC in the thyroid tumoral tissue, as ret/PTC1 isoform. Either APC has a tissue-specific dominant effect in the thyroid gland or the germline mutation confers a generic susceptibility to cancer development, but other factors (sex-related factors, environmental radiation, modifier genes) are also required for TC development. This usually involves ret/PTC activation, suggesting a possible cooperation between altered function of APC and gain of function of ret.

Adenomatous Polyposis Coli↗
PubMed1999

K-ras mutation and loss of heterozygosity of the adenomatous polyposis coli gene in patients with colorectal adenomas with in situ carcinoma.

BACKGROUND: The majority of colorectal carcinomas, if not all, arise from a benign adenoma. The DNA of the carcinomatous cells frequently has mutations in several genes. However, it is not exactly clear when during the neoplastic process each mutation develops. An adenoma with an area of in situ carcinoma provides an opportunity to evaluate genetic changes within a single neoplasia whose separate areas are comprised of both the benign adenoma as well as the malignant carcinoma. METHODS: Thirty-seven neoplasms with areas of both benign adenoma and in situ carcinoma were studied. Both portions were evaluated for loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene and for mutations in codons 12/13 of the K-ras oncogene using the polymerase chain reaction technique. RESULTS: Twenty-eight neoplasms showed no LOH in either portion whereas both portions of 4 neoplasms revealed a loss of heterozygosity. In three lesions the APC gene was normal in the adenomatous portion but LOH was present in the carcinomatous portion. Two neoplasms were uninformative for LOH of the APC gene. Thirteen neoplasms showed the wild-type pattern for the K-ras oncogene whereas 15 contained the identical mutation in both portions. Of the remaining nine neoplasms, six had a K-ras mutation in the adenomatous portion only and three had one pattern in the adenomatous portion and a different pattern in the in situ carcinoma portion. CONCLUSIONS: LOH of the APC gene is an early and persistent feature in the evolution of a benign colorectal adenoma into an in situ carcinoma. There is less consistency regarding K-ras mutations; one in five in situ carcinomas contains a K-ras mutation different from that observed in the adenomatous portion.

Adenomatous Polyposis Coli↗
PubMed1995

The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia.

Mutations in the APC gene are responsible for various familial and sporadic colorectal cancers. Min mice carry a dominant mutation in the homolog of the Apc gene and develop multiple adenomas throughout their small and large intestine. Quantitative trait loci studies have identified a locus, Mom1, which maps to the distal region of chromosome 4, that dramatically modifies Min-induced tumor number. We report here the identification of a candidate gene for Mom1. The gene for secretory type II phospholipase A2 (Pla2s) maps to the same region that contains Mom1 and displays 100% concordance between allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1 susceptible strains are most likely null for Pla2s activity. Our results indicate that Pla2s acts as a novel gene that modifies polyp number by altering the cellular microenvironment within the intestinal crypt.

Adenomatous Polyposis Coli↗