Typical Familial Adenomatous Polyposis Research Articles

Molecular analysis of the APC gene in Sicilian patients with familial adenomatous polyposis (F.A.P.)

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported.In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment.We have detected different APC mutations in these five pedigrees, confirming the remarkable heterogeneity of the mutational spectrum in FAP.

Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with almost 100 % risk of colorectal cancer. The typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by extracolonic manifestations, later onset and lower number of polyps in colon is characteristic of an attenuated form (AFAP). We analyzed the APC gene for germline mutations in 90 FAP/AFAP patients. Mutation screening was performed using Denaturing Gradient Gel Electrophoresis. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. APC-mutation-negative probands were screened for large deletions of the APC gene using multiplex ligation dependent probe amplification. Analysis of mRNA variants followed in probands with possible splicing mutation by PCR amplification of target site flanking exons and sequencing the normal and aberrant products. We identified 30 germline variants among 36 unrelated probands including large deletions. Eleven APC variants detected last two years have not been reported yet. At all, fifteen of them are expected to cause errors in mRNA splicing. Analysis of mRNA in ten of these patients revealed exon skipping in seven cases, exonisation of intron in one of these as well, change of the amount of alternatively spliced product in one case, and no effect was found in three cases. In two of the patients, the biopsy of colon mucosa and polyp enabled us to examine the effect of the mutation on splicing pattern in colon cells directly. The comparison of alternative and standard transcript amount showed similar transcription pattern of exon 14 in control colon mucosa tissue (9 samples) as in 51 blood control samples.

Guidelines for the clinical management of familial adenomatous polyposis (FAP)

Background: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds...

The patient with multiple intestinal polyps

The management of patients with multiple intestinal polyps may be difficult and greatly depends on the correct classification. Polyposis syndromes account for less than 1% of newly diagnosed colorectal cancers. In addition the risk for extracolonic cancer is increased in most syndromes. Here we report the case of a difficult patient with severe gastric polyposis and we present a review of polyposis syndromes such as classical and attenuated familial adenomatous polyposis (FAP), MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis as well as rare polyposis syndromes. The most practical approach for the diagnostic workup in patients with newly diagnosed gastrointestinal polyposis is based on the histological typing of polyps. In addition, a detailed family history regarding cancer, polyps and congenital abnormalities should be obtained from every polyposis patient. Patients with multiple adenomas are most likely to suffer from FAP, AFAP or MAP. Of these, younger age and higher polyp count are most likely a diagnosis of typical FAP. Older age and fewer polyps favour a diagnosis of AFAP or MAP. Germline testing of the APC gene is suggested, and if negative, MYH gene testing should be done. In patients with hamartomas, extraintestinal features should be evaluated and reference histology should be initiated. In addition panintestinal imaging should be performed with EGD, colonoscopy and small bowel imaging (PE, CE, and MR) enteroclysis. For diagnostic and therapeutic problems a familial colorectal cancer center should be consulted. Using this algorithm, correct classification and adequate treatment should be possible for every polyposis patient.

Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects

BackgroundGermline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease.MethodsHere, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346.ResultsIn the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease.ConclusionThe results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care.

Different familial adenomatous polyposis phenotypes resulting from deletions of the entire APC exon 15

Germline mutations of the adenomatous polyposis coli ( APC) gene cause familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease that predisposes patients to colorectal cancer. The APC gene is composed of 15 coding exons and encodes an open reading frame of 8.5 kb. The 3' 6.5 kb of the APCopen reading frame is encoded by a single exon, exon 15. Most identified APC mutations are at the 5' half of the APC open reading frame and are nucleotide substitutions and small deletions or insertions that result in truncation of the APC protein. Very few well-characterized gross alterations of APC have been reported. Patients with FAP typically develop hundreds to thousands of colorectal tumors beginning in their adolescence. A subgroup of patients with FAP who develop fewer tumors at an older age have what is called attenuated FAP (AFAP). Accumulating evidence indicates that patients carrying germline APC mutations in the first four coding exons, in the alternatively spliced region of exon 9, or in the 3' half of the coding region usually develop AFAP. We characterized two germline APC alterations that deleted the entire APC exon 15 as the result of 56-kb and 73-kb deletions at the APC locus. A surprising finding was that one proband had the typical FAP phenotype, whereas the other had a phenotype consistent with that of AFAP.