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PubMed1995

Haplotype comparison in fresh mutation cases of adenomatous polyposis coli due to deletion AAAGA at codon 1309.

To determine whether the common 5 base pair deletion (delta AAAGA) at codon 1309 of the APC gene occurs preferentially on a particular haplotype background, three intragenic polymorphisms were typed using the polymerase chain reaction in ten patients with this deletion as the disease-causing mutation. Each case was due to fresh mutation. The data obtained provide no evidence in support of a preferential haplotype predisposing to this mutation.

Base Sequence↗
PubMed2006

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype-phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10-12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.

Adenomatous Polyposis Coli↗
PubMed1996

Florid oral manifestations in an atypical familial adenomatous polyposis family with late presentation of colorectal polyps.

Early identification and prophylactic surgery are essential in preventing development of malignancy in colorectal polyps in familial adenomatous polyposis (FAP). Previous studies indicate a 100% cumulative risk of developing colonic polyps in individuals with FAP by the age of 34 yr. However, we have previously reported late-onset and non-penetrance of polyposis in four families. We describe here in detail one of these families with florid oral manifestations detectable on panoramic radiography of the jaws, which were instrumental in the diagnosis of FAP in the index patient and for ascertainment of her family for screening. The pathological adenomatous polyposis coli (APC) gene mutation in this family was shown to segregate with dento-osseous changes. Panoramic jaw radiography is a common examination carried out prior to dental or oral surgical procedures. This case illustrates the importance of appropriate investigations, including family history and colonoscopy, even in relatively older patients with radiological findings such as those described here and in members of their families at risk of FAP.

Adenomatous Polyposis Coli↗
PubMed2002

Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice.

The mammalian protein MBD4 contains a methyl-CpG binding domain and can enzymatically remove thymine (T) or uracil (U) from a mismatched CpG site in vitro. These properties suggest that MBD4 might function in vivo to minimize the mutability of 5-methylcytosine by removing its deamination product from DNA. We tested this hypothesis by analyzing Mbd4-/- mice and found that the frequency of of C --> T transitions at CpG sites was increased by a factor of three. On a cancer-susceptible Apc(Min/+) background, Mbd4-/- mice showed accelerated tumor formation with CpG --> TpG mutations in the Apc gene. Thus MBD4 suppresses CpG mutability and tumorigenesis in vivo.

5-Methylcytosine↗
PubMed1997

An unusually severe phenotype for familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance.

Adenomatous Polyposis Coli↗
PubMed1997

Severe upper gastrointestinal polyposis associated with sparse colonic polyposis in a familial adenomatous polyposis family with an APC mutation at codon 1520.

BACKGROUND: Familial adenomatous polyposis usually results in colonic polyposis with hundreds to thousands of polyps, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and variable extracolonic features. Recent reports indicate that patients with distal mutations between codons 1445 and 1578 do not express CHRPE and have a high incidence of desmoid tumours. PATIENTS: The family studied has an unusual phenotype of sparse colonic polyposis but profuse upper gastrointestinal polyposis. Affected subjects do not have CHRPE. METHODS: The protein truncation test followed by sequencing identified a 2 base pair deletion at codon 1520 in the APC gene. This results in a frameshift creating a stop codon 13 codons downstream. RESULTS: This family demonstrates that sparse colonic polyposis but severe upper tract polyposis may be associated with mutations between codons 1445 and 1578. CONCLUSIONS: Study of duodenal and colonic polyps in further cases with mutations in this region is warranted. Such mutations may preferentially cause duodenal adenomas and desmoid tumours as somatic mutations in these tumours also occur in this region, unlike colorectal tumours where somatic mutations occur more proximally. This study emphasises the importance of screening the upper gastrointestinal tract even when the colonic disease is mild.

Adenomatous Polyposis Coli↗
PubMed1996

Molecular screening of families affected by familial adenomatous polyposis (FAP).

OBJECTIVES: To assess the risk of developing familial adenomatous polyposis (FAP) in presymptomatic individuals using APC gene flanking and intragenic polymorphic markers. SETTING: Twenty families enrolled in the Italian Registry of Polyposis comprising a total of 217 individuals, including 53 (24%) presymptomatic subjects with a 50% a priori risk of FAP, were analysed. Direct analysis techniques had previously failed to identify the FAP mutation in these families. METHODS: DNA isolated from peripheral mononuclear blood cells and tissue sections was analysed by the polymerase chain reaction and a panel of seven highly polymorphic markers--YN5.64, CB83, CB26, LNS, APC1458.5, MBC, 37AB. Amplification products were separated by a modified denaturing gel electrophoresis method. RESULTS: The haplotype associated with the disease was identified in 18 families (90%). The segregation of the FAP haplotype in these kindreds showed that 10 presymptomatic individuals had inherited the FAP mutation and carried a high risk of developing the disease. The remaining two families were not informative because of the lack of a sufficient number of probands or biological specimens. CONCLUSIONS: These data indicate that indirect analysis with linked DNA markers has a high rate of success in defining the risk of FAP of presymptomatic subjects, provided that a sufficient number of probands or samples is available. Uninformative families accounted for 10% of the total, indicating that linkage analysis may still have higher sensitivity than direct mutation analysis techniques. The combined use of both approaches should be implemented, however, to enhance further the application of molecular genetics to the screening of families with FAP.

Adenomatous Polyposis Coli↗
PubMed2004

Papillary thyroid carcinoma associated with familial adenomatous polyposis: molecular analysis of pathogenesis in a family and review of the literature.

We found a case of a papillary thyroid carcinoma that was accompanied by a familial adenomatous polyposis (FAP) in a 29-year-old female. She had hundreds of adenomas inside the entire colon and a congenital hypertrophy of the retinal pigmented epithelium (CHRPE). The patient underwent a total thyroidectomy and a central compartment neck node dissection. Gross examination of the thyroid identified two solid and cystic lesions. The pathological finding of thyroid cancer revealed a mixture of a peculiar nuclear clearing, cribriform, morula formation, trabecular and papillary pattern. The patient's brother had undergone a total colectomy due to FAP at the age of 25. Genetic analyses of the patient's family members revealed that she and her brother had the same germline mutation, in which five nucleotides (AAAGA) were deleted from codon 1309 of the adenomatous polyposis coli (APC) gene exon 15. Strong and frequent immunoreactivities of beta-catenin and p53 were evident in the tumor tissue. At the time of writing, a preventive colectomy was still under consideration for the patient. Genetic counseling was given to the other family members, who were not attacked by this disease, in order to allay their fears of cancer.

Adenomatous Polyposis Coli↗
PubMed2004

Prevention of colorectal cancer using COX-2 inhibitors: basic science and clinical applications.

Cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in pre-neoplastic tissues and several human cancers including colorectal cancer. Evidence linking COX-2 activity to carcinogenesis was derived from epidemiologic studies and animal models with defect adenomatous polyposis coli (APC) gene. PGE2 induced by COX-2 exerts several biological properties that may be advantageous for tumorigenesis: 1) Promoting angiogenesis (increased VEGF, bFGF, and PDGF production), 2) Anti-apoptosis mechanism (via increased bcl-2 and Akt activity), 3) Stimulating tumor metastasis (by increasing matrix metalloproteinases) and 4) Decreased immune surveillance (decreased cytokine production and NK activity). In addition, COX-2 reaction can cause DNA oxidation and induce mutations. Chemoprevention of colorectal cancer has attracted great attention in recent years. Epidemiologic data showed that chronic intake of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce the incidence of colorectal cancer. Recent clinical trial studies showed that celecoxib, a selective COX-2 inhibitor, is equally effective in reducing colorectal adenomas in animal models and patients with familial adenomatous polyposis (FAP), yet with superior GI safety. Two COX-2 inhibitors (celecoxib and refocoxib) have been approved by FDA as adjuncts to usual care in FPA patients, and are currently being studied in patients with sporadic adenomas and other types of cancers. These studies are expected to generate evidence in favor of targeting COX-2 and its gene products as chemopreventive strategies, which may provide an alternative in current approach to reducing the morbidity and mortality of this disease.

Adenomatous Polyposis Coli↗
PubMed1999

Beta-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas.

Loss of serine or threonine phosphorylation sites from exon 3 of beta-catenin has been identified in approximately half of colorectal tumors which lack adenomatous polyposis coli (APC) mutations, but the overall contribution of beta-catenin mutations to sporadic colorectal tumorigenesis is unclear. We therefore used PCR to amplify and sequence exon 3 of beta-catenin from 202 sporadic colorectal tumors. Exon 3 beta-catenin mutations were identified in 6 of 48 small (< 1 cm) adenomas, 2 of 82 large (> or =1 cm) adenomas, and 1 of 72 invasive carcinomas. Eight of the nine mutations, including all of those in the small adenomas and the invasive cancer, involved loss of serine or threonine phosphorylation sites. The percentage of beta-catenin mutations in small adenomas (12.5%) was significantly greater than that in large adenomas (2.4%) and invasive cancers (1.4%; P = 0.05 and P = 0.02, respectively). We conclude that mutation of beta-catenin can be an early, perhaps initiating, event in colorectal tumorigenesis. Small adenomas with beta-catenin mutations do not appear to be as likely to progress to larger adenomas and invasive carcinomas as other adenomas, however, with the result that beta-catenin mutations are only rarely seen in invasive cancers. This suggests that APC and beta-catenin mutations are not functionally equivalent, and that the APC gene may have other tumor suppressor functions besides the degradation of beta-catenin.

Adenoma↗
PubMed2000

[Clinical features and current progress of familial adenomatous polyposis].

Familial adenomatous polyposis(FAP) is inherited disease as an autosomal dominant trait in which the large intestine is diffusely carpeted by numerous adenomas with a high incidence of colorectal cancer. Current clinical aspects and biological progress were discussed with emphasis on diagnostic imaging, natural histories of gastrointestinal polyps and intra-mandibular osteomas. Genotype-phenotype correlation including attenuated type and function of APC gene, identified in 1991 as a responsible tumour suppressor one for FAP and Gardner syndrome, were also reviewed.

Adenomatous Polyposis Coli↗
PubMed2002

[Familial adenomatous polyposis (FAP)--diagnosis and management].

Familial adenomatous polyposis (FAP) is characterized by more than hundreds of colorectal adenomas, colorectal cancer in early adult life, extracolonic features and genetic inheritance. Not only surgical management of FAP (IAA, IACA and IRA) but also methodology of APC gene test is almost established. Surveillance program and management of extracolonic manifestation is going to contribute to patient's prognosis. And now in Japan, two clinical intervention and chemoprevention trial studies of FAP are going on. As these reasons, FAP is most comprehensive model for understanding status quo and future problem of familial cancer syndromes. However, there are many counseling issues of FAP family members, choice of opportunity and method for diagnosis, surveillance, chemoprevention, surgery and to inform family member about hereditary risk. So, Cancer Genetic Counseling for FAP family members must be provided for their lifetime long.

Adenomatous Polyposis Coli↗
PubMed2002

[Recent advances in the diagnosis and treatment of colorectal cancers].

We review recent developments in the diagnosis and treatment of colorectal cancer. In diagnosis, the detection of the APC gene mutation in stool samples has had a strong impact because of its practical usage for mass screening. Several reports have indicated that the molecular detection of a very small number of cancer cells in the peripheral blood, bone marrow, or lymph nodes yields adequate information on recurrent disease. Several new markers were reported as a significant indicators of cancer development, invasion, or metastasis. In treatment, determination of microsatellite instability may be useful to select good candidates for 5-fluorouracil-based chemotherapy. New molecular targets have been reported, including epidermal growth factor receptor inhibitor, matrix metalloproteinase inhibitors, etc. Gene therapy with p53 or FHIT had undergone successful clinical trials. Tumor-specific immunotherapy with dendritic cell vaccination has also been achieved. In conclusion, many efforts to overcome colorectal cancer will soon open new therapeutic windows.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

[Desmoid tumors in patients with familial adenomatous polyposis].

Desmoid tumours (DT) are slow-growing tumours that consist of proliferations of well-differentiated fibroblasts. Although the typical characteristics of malignant tumours, such as distant metastases, are absent, the tumours are locally aggressive and grow into neighbouring structures. The prevalence of desmoid tumours in patients with FAP is 7-12%. The lifetime risk of developing desmoid tumours is about 20%. In FAP, most tumours are intra-abdominal or located in the abdominal wall. Next to colorectal cancer, desmoid tumours are the most frequent cause of death in FAP. Possible risk factors for the development of desmoid tumours are previous surgical procedures, pregnancy, female sex, a family history of desmoid tumours, and specific mutations in the APC-gene. Both CT scanning and MRI can be used to detect the tumours. An excision biopsy is needed to establish the diagnosis. Medicinal treatment with NSAIDs is the treatment of first choice, followed by hormonal treatment (e.g., tamoxifen) in combination with NSAIDs. Both forms of treatment lead to a response in about 30-50% of the patients. Surgery is the preferred treatment for extra-abdominal tumours or tumours located in the abdominal wall. Surgical treatment of intra-abdominal tumours is only indicated in patients with obstruction of the bowel or ureter. Chemotherapy is indicated in patients with progressive desmoid tumours when non-cytotoxic treatment has failed. Radiotherapy may play a role in the treatment of irresectable extra-abdominal or abdominal wall tumours, or as adjuvant treatment of tumours with positive margins.

Abdominal Neoplasms↗
PubMed2003

Cribriform-morular variant of papillary carcinoma: the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma. A case report with clinical and molecular genetic correlation.

The increased incidence of thyroid carcinomas in familial adenomatous polyposis (FAP) patients is well recognised. These thyroid neoplasms display distinctive clinicopathological features and generally show good prognostic outcome. Recently, unusual sporadic tumours that share the morphological features of FAP-associated thyroid carcinomas have also been described. In this report, we document a case of a thyroid tumour in a previously well, 46-year-old female. Histology revealed a circumscribed neoplasm composed of tubular, papillary, cribriform and solid areas. The pseudostratified columnar tumour cells showed occasional nuclear grooves and rare nuclear inclusions. Immunohistochemistry showed positive staining with antibodies to cytokeratin AE1/AE3, oestrogen and progesterone receptor proteins. Focal immunoreactivity was also noted with antibodies to thyroglobulin, epithelial membrane antigen, 34betaE12 and cytokeratin CK7. The absence of polyps on colonoscopy and germline mutation in the adenomatous polyposis coli (APC) gene provides evidence that this tumour represents the sporadic counterpart of FAP-associated thyroid carcinoma. The patient is well with no evidence of disease 7 months following resection of the tumour. The differential diagnoses and molecular genetics of this unusual tumour are discussed.

Adenocarcinoma, Papillary↗
PubMed2004

Familial polyposis coli: clinical manifestations, evaluation, management and treatment.

Familial adenomatous polyposis (FAP) is an autosomal dominant, hereditary colon cancer syndrome that is characterized by the presence of innumerable adenomatous polyps in the colon and rectum. Gardner's syndrome is a variant of FAP, which in addition to the colonic polyps, also presents extracolonic manifestations, including desmoid tumors, osteomas, epidermoid cysts, various soft tissue tumors, and a predisposition to thyroid and periampullary cancers. Mutations of the APC gene are thought to be responsible for the development of FAP, and the location of the mutation on the gene is thought to influence the nature of the extracolonic manifestations that a given patient might develop. Though patients are often asymptomatic, bleeding, diarrhea, abdominal pain and mucous discharge frequently occur. Diagnostic tools include genetic testing, endoscopy, and monitoring for extra-intestinal manifestations. Currently, surgery is the only effective means of preventing progression to colorectal carcinoma. Restorative proctocolectomy with ileal pouch anal anastomosis (RPC/IPAA) with mucosectomy is the preferred surgical procedure, since it attempts to eliminate all colorectal mucosa without the need for an ostomy. Periampullary carcinoma and intra-abdominal desmoid tumors are a significant cause of morbidity and mortality in these patients after colectomy. Frequent endoscopy is needed to prevent the former, while there is no definitive treatment available yet for the latter. The following article presents a case and reviews the evaluation, management and treatment of Gardner's syndrome.

Adenomatous Polyposis Coli↗
PubMed2004

Influence of diet containing lyophilized Enterococcus faecium M-74 with organic selenium on tumor incidence in Apc1638N mice.

The aim of the present study was to test the effect of long-term application of diet containing Enterococcus faecium M-74 with organic selenium on tumor induction in transgenic mice carrying mutation in Apc gene. Heterozygosity for the Apc1638N mutation in mice causes development of small intestine and gastric tumors. Feeding of Apc1638N transgenic mice with enriched diet with probiotic components during 8 months have shown a minor therapeutic effect on the clinical manifestations in small intestine in comparison with control group.

Adenocarcinoma↗
PubMed1989

[The polyposis project].

A research project initiated in 1978 comprised establishment of a national polyposis registry, a genetic linkage study using classical and DNA markers, an in vitro study of fibroblasts for transformation parameters and chromosome instability, and a comparative study of DNA-RFLPs in cancer and constitutional tissue. The linkage study (to be reported elsewhere) confirmed the recently reported close linkage between the polyposis gene locus APC and D5S71. No in vitro test for the presence of the APC gene has been confirmed or revealed, but we detected increased chromosomal instability on a statistical basis and also recorded abnormal DNA-repair. As per 1. January 1988 the prevalence of adenomatosis of colon and rectum in Norway was 1/43,500. Among patients born in the period 1931-1950 the incidence at birth of developing the disease is 1/20,000 and the mutation rate is 1/72,000 per gamete per generation. In Norway new mutants in healthy families will comprise 1/3-1/2 of all new cases in the coming two decades, or one of 36,000 births.

Adenomatous Polyposis Coli↗