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At least 19 recordsLinked to original sources
PubMed2002

The most frequent APC mutations among Slovak familial adenomatous polyposis patients. Adenomatous polyposis coli.

We screened 46 suspected families from whole Slovakia for familial adenomatous polyposis (FAP) cancer predisposition. Individuals were enrolled to the adenomatous polyposis coli (APC) gene mutations mapping program at the base of previous clinical investigation. We have used the following techniques: heteroduplex analysis (HDA), protein truncation test (PTT), single strand conformation polymorphism (SSCP) and sequencing for the identification and detailed positional analysis of APC mutations. Around 90% of all detected mutations were found being truncated. The most frequent mutations from this collection were located within codons 1309 and 1061 of exon 15 and represented 15% and 7%, respectively of all tested families. The expressive phenotype, large amount of colorectal polyps and congenital hypertrophy of the retinal pigment epithelium (CHRPE) were associated to all mutations within codons 1309 and 1060.

Adenomatous Polyposis Coli↗
PubMed2001

Profuse familial adenomatous polyposis with an adenomatous polyposis coli exon 3 mutation.

The attenuated form of familial adenomatous polyposis coli (AAPC) is associated with mutations in the adenomatous polyposis coli (APC) gene which cluster in the 5' region of the gene. It has been proposed that a 'genotype-phenotype boundary' exists at codons 159-163, and mutations that are 5' of this boundary will produce AAPC. Herein we document a three-generation family with an exon 3 mutation well to the 5' side of the proposed boundary, in which two affected individuals have had, in their 40s, a profuse form of familial adenomatous polyposis coli. We conclude that the codon 159-163 'boundary' is indicative rather than definitive. These two patients also had postoperative intra-abdominal adhesions, severely so in one.

Adenomatous Polyposis Coli↗
PubMed2002

APC gene mutations in a jejunal adenoma causing intussusception in a patient with familial adenomatous polyposis.

Adenomatous polyps of the jejunum/ileum in patients with familial adenomatous polyposis (FAP) are usually small (<5 mm) and are considered to be of little clinical importance. Genetic alterations in these polyps have not previously been analyzed. We herein report an extremely rare case of FAP presenting with intussusception caused by jejunal adenomas. Both somatic and germline mutations of the APC gene were detected in one of the polyps. A 40-year-old man with FAP was admitted for closure of an ileostomy that had been created because of an anastomotic leak after subtotal proctocolectomy with ileo-anal-canal anastomosis. During the follow-up after that surgery, he had occasionally complained of colicky abdominal pain, but it had quickly subsided. At the second laparotomy, for closure of the ileostomy, jejuno-jejunal intussusception was incidentally found, and segmental resection of the jejunum, including the leading point of the intussusception, was performed. There were five polyps clustered in the resected jejunum. Histologically, the polyps, ranging from 5 to 26 mm in diameter, were adenomas with moderate to severe atypia. Genetic examinations of one of the largest polyps, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and direct sequencing methods, revealed somatic (T insertion at codon 1557) and germline mutations (4 base-pair deletion at codons 181-182) of the APC gene. This is the first evidence that the coexistence of somatic and germline alterations in the APC gene is involved in the development of a jejunal adenoma causing small-bowel intussusception.

Adenoma↗
PubMed1997

Childhood hepatocellular adenoma in familial adenomatous polyposis: mutations in adenomatous polyposis coli gene and p53.

BACKGROUND & AIMS: Infantile and childhood liver tumors have been found in 0.42% of individuals with a germline mutation in the adenomatous polyposis coli (APC) gene. This study analyzed a hepatocellular adenoma of a 2-year-old child at risk for familial adenomatous polyposis to identify genetic alterations in hepatic tumors initiated by APC germline mutations. METHODS: Mutation screening was performed for the APC gene (protein truncation test and DNA sequence analysis), p53 gene (complementary DNA cloning and sequencing), and members of the Ras gene family (complementary DNA sequence analysis). RESULTS: Both the mother and child had a germinal CGA-->TGA transition at codon 1451 leading to an Arg1451Ter stop mutation in the APC gene. Loss of the wild-type APC allele as a second hit revealed hemizygosity of the inherited mutation in the tumor. Furthermore, a CGC-->CAC transition in the p53 gene of the adenoma resulted in an Arg-->His missense mutation in codon 175. No loss of heterozygosity was detected at the p53 locus. Ras gene mutations were not found. CONCLUSIONS: Biallelic inactivation of APC gene and p53 mutation are early events in hepatocellular tumorigenesis. Additional reports will confirm whether inherited APC gene mutations between codon 1444 and 1578 increase the risk for hepatic tumors.

Adenoma, Liver Cell↗
PubMed1992

Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus.

Adenomatous polyps are an intermediate in the pathway to colon carcinoma. An inherited disorder, familial adenomatous polyposis coli (APC), is characterized by hundreds to thousands of adenomatous polyps. A previously reported family had colon cancer associated with a low average but highly heterogenous number of colonic polyps, this phenotype mapped to the APC locus on 5q. Four new families have been ascertained in which the phenotypic pattern was different from classical polyposis but similar to that of the "prototype" kindred reported earlier. By multilocus linkage analysis, the gene responsible for the disease phenotype was mapped, with a high level of confidence, to the APC locus in two of the four families with the attenuated or variant form of polyposis (AAPC); the results for the two remaining kindreds were inconclusive. A combined maximum LOD score of approximately 7.6 at a recombination fraction of 0 was obtained when the results were summed over the four pedigrees with markers closest to the APC locus. The establishment of genetic linkage in such families may point to the APC locus as having a more significant role in inherited predispositions to colorectal cancer than was previously thought.

Adenomatous Polyposis Coli↗
PubMed2002

Molecular diagnosis of familial adenomatous polyposis (FAP): genotyping of adenomatous polyposis coli (APC) alleles by MALDI-TOF mass spectrometry.

OBJECTIVES: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposition syndrome caused by germ line mutations in the adenomatous polyposis coli gene (APC). For prophylactic colectomy, timely identification of patients at risk is urgent. Here, matrix assisted laser desorption ionization - time of flight - mass spectrometry (MALDI-TOF-MS) genotyping is offered for an efficient molecular diagnosis of APC germline mutations. DESIGN AND METHODS: The four most frequent APC germ line mutations (three deletions, one point mutation) were genotyped by allele specific elongation and termination of extension primers. The extension products generated were analyzed by MALDI-TOF-MS. RESULTS: Following PCR amplification and allele specific primer extension reactions MALDI-TOF-MS allowed the unambiguous identification of informative nucleic acid fragments corresponding to distinct genotypes or mutants even in duplex assays. Results were confirmed by DNA-sequencing. CONCLUSIONS: Due to its high molecular resolution and accuracy, this method is highly suitable as an alternative for clinical APC genotyping.

Adenomatous Polyposis Coli↗
PubMed2006

Singapore familial adenomatous polyposis (FAP) patients with classical adenomatous polyposis but undetectable APC mutations have accelerated cancer progression.

OBJECTIVES: Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAP patients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAP patients with and without detectable APC mutations. METHODS: We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. RESULTS: APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. CONCLUSIONS: We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.

Adenomatous Polyposis Coli↗
PubMed2000

Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations.

Fundic gland polyps (FGPs) are the most common gastric polyps in patients with familial adenomatous polyposis (FAP). FGPs have traditionally been regarded as nonneoplastic, possibly hamartomatous lesions, but the pathogenesis of FGPs in both FAP and sporadic patients remains unclear. FGPs in FAP can show foveolar dysplasia, and rarely invasive gastric adenocarcinoma has been reported in patients with FAP and fundic gland polyposis. Using direct gene sequencing and allelic loss assays at 5q, we analyzed somatic adenomatous polyposis coli (APC) gene alterations in 41 FAP-associated FGPs (20 with foveolar dysplasia, six indefinite for dysplasia, and 15 nondysplastic) and 13 sporadic FGPs. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 25 of 41 FAP-associated FGPs and 13 of 13 sporadic FGPs. Somatic APC gene alterations were identified frequently (21 of 41 cases, 51%) in FAP-associated FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the FGPs were shown to carry the same somatic APC gene alteration in 24 (96%) of 25 cases. Furthermore, there was no difference in the frequency of somatic APC gene alterations between FGPs with foveolar dysplasia (10 of 20, 50%), indefinite for dysplasia (four of six, 67%), and nondysplastic (seven of 15, 47%) in FAP patients (P: = 0.697). In contrast, FGPs from non-FAP patients showed infrequent (one of 13, 8%) APC gene alterations (P: = 0.008). These results show that FGPs in FAP patients are pathogenetically distinct from sporadic FGPs. Somatic, second-hit APC gene alterations, which precede morphological dysplasia in many FAP-associated FGPs, indicate that FGPs arising in the setting of FAP are neoplastic lesions.

Adenomatous Polyposis Coli↗
PubMed1992

Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients.

Mutation and loss of heterozygosity (LOH) in the p53 gene were analyzed in 274 colorectal tumors of 4 histopathological grades. Among 160 tumors from 40 familial adenomatous polyposis patients, none of 58 adenomas with moderate dysplasia had p53 mutations, whereas 8% (3 of 37) of severe adenomas, 15% (6 of 40) of intramucosal carcinomas, and 40% (10 of 25) of invasive carcinomas had p53 mutations. Only 3% (1 of 33) of severe adenomas showed both mutation and LOH, while 25% (6 of 24) of intramucosal carcinomas and 40% (10 of 25) of invasive carcinomas had both mutation and LOH. All intramucosal and invasive carcinomas that had mutations lost the other allele of the p53 gene. In 114 tumors from 86 non-familial adenomatous polyposis patients, similar results were obtained; no adenoma showed both mutation and LOH, but both alterations occurred in intramucosal and invasive carcinoma. As regards specificity in 56 mutations detected in the present study, the frequently affected codons were codons 175, 238, 245, 248, 273, and 282, 4 of these amino acids being arginine, and 72% (39 of 54) of all mutations were GC to AT transition. Although expression into p53 polyadenylated RNA was high in every invasive carcinoma irrespective of the presence of mutation or LOH, there was a correlation between mutation and protein level; immunostaining of p53 protein was negative in almost all adenomas, but it was positive in 86% of invasive carcinomas exhibiting p53 mutation. These data suggest that genetic changes on both alleles of the p53 gene through mutation and LOH, which result in abnormal protein accumulation, are involved in the conversion of adenoma to early carcinoma. Also, carcinoma cells with p53 mutations existing within adenoma tissues are detectable by immunostaining, even in formalin-fixed, paraffin-embedded specimens.

Adenoma↗
PubMed1992

Risk estimation in familial adenomatous polyposis using DNA probes linked to the familial adenomatous polyposis gene.

The familial adenomatous polyposis gene has recently been assigned to the long arm of chromosome five through linkage to several 5q DNA probes. These probes can now be used to trace inheritance of the disease gene in affected families. In this study, DNA samples from 152 members of 10 Australian familial adenomatous polyposis families have been examined for restriction fragment length polymorphisms detected by DNA probes C11P11, ECB27, and YN5.48. Linkage analysis confirmed linkage between the familial adenomatous polyposis gene and each probe with a maximum combined LOD score of 2.82 for C11P11, 2.90 for ECB27 and 5.49 for YN5.48 all at a recombination fraction of zero. Risk estimates were determined for the 51 at risk individuals in these families based on their restriction fragment length polymorphism data alone or in addition by including the effect of age dependent penetrance. Thirty two of those at risk (63%) could be assigned specific high (greater than or equal to 95%) or low (less than or equal to 5%) risks of developing familial adenomatous polyposis on the basis of their probe results. When the effect of age dependent penetrance was included, 26 (51%) fell at the extremes of risk (greater than or equal to 99% or less than or equal to 1%). Such estimates provide a sound basis for planning sigmoidoscopic screening of at risk family members and will thus facilitate surveillance in familial adenomatous polyposis families.

Adenomatous Polyposis Coli↗
PubMed1992

Loss of expression of the DCC gene during progression of colorectal carcinomas in familial adenomatous polyposis and non-familial adenomatous polyposis patients.

We have previously observed that the frequency of loss of heterozygosity (LOH) on chromosome 18q was low in adenomas and intramucosal carcinomas, whereas invasive carcinomas exhibited a high frequency in familial adenomatous polyposis patients (M. Miyaki et al., Cancer Res., 50: 7166-7173, 1990). In the present study, LOH at the DCC locus on chromosome 18q and the expression of DCC gene into mRNA were analyzed in colorectal tumors with distinct histopathological types. The carcinomas that showed 18q LOH also lost the DCC locus. The expression of DCC gene into mRNA was examined at the level of 233-base pair fragments of nucleotide 986-1218 in DCC complementary DNA. In a moderate-to-severe adenoma, 5 carcinoma-in-adenomas, and 4 intramucosal carcinomas, the level of expression was as high as in normal colorectal mucosa, whereas it was greatly reduced or not detectable in most (13 of 16) invasive carcinomas. Among these invasive carcinomas, 7 of 11 showed 18q LOH, but 4 showed no LOH. These results suggest that the DCC gene is included in the allelic deletion on chromosome 18q, and that the progression of colorectal carcinoma from early stage to advanced stage accompanies the inactivation of the DCC gene through LOH and other mechanisms.

Adenoma↗
PubMed2006

[Clinical management of adenomatous polyposis in patients with hereditary non-polyposis colorectal cancer and familial adenomatous polyposis].

OBJECTIVE: To investigate the validity and safety of different doses of non-steroidal anti-inflammatory drugs (NSAID) in attempting to maintain the regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: Twenty-two FAP patients who were willing to receive celecoxib were randomly divided into 2 groups 400 mg/d group (n = 8, taking celecoxib 400 mg/d) and 200 mg/d group (n = 10, taking celecoxib 200 mg/d). Four FAP patients who refused celecoxib and selected aspirin 80 mg/d instead. Six HNPCC patients were given celecoxib 400 mg daily. The treatment lasted for 24 months in all groups. The efficacy was evaluated respectively by the number and grade of polyps by coloscopy every 3 months in the first year and every 6 months in the second year. RESULTS: Either dose of celecoxib could reduce polyps in the FAP patients, with a polyps reduction rate of 86.6% (280/323) in the 400 mg group, significantly higher than that in the 200 mg group [51.81% (129/249) of the aspirin group]. In 5 of the 6 HNPCC patients the polyps completely vanished after 9 months of treatment. Side effects, such as arrhythmia, angina pectoris, and nervous headache, were observed in the celecoxib 400 mg/d group. The side effects could be reversed by decreasing the dose of celecoxib or using aspirin instead. Only one patient in the celecoxib 200 mg/d group showed side effects. CONCLUSION: Celecoxib 400 mg daily is more effective but has more side effects. At first the patients should be treated with celecoxib 200 mg daily for a long time, or 400 mg/d in the first 6 months and then with a daily dose of 200 mg/d to maintain the treatment effects. Soluble aspirin has similar effects.

Adenomatous Polyposis Coli↗
PubMed1998

Prophylactic pancreaticoduodenectomy for premalignant duodenal polyposis in familial adenomatous polyposis.

The frequency of duodenal adenomas in patients with, familial adenomatous polyposis is high. Duodenal adenoma has malignant potential, and duodenal adenocarcinoma is one of the main causes of death in patients who have had previous proctocolectomy. A conservative approach to the treatment of duodenal adenomas (nonsteroidal anti-inflammatory drugs, endoscopy, polypectomy through duodenotomy) is inefficient and unsafe. When invasive cancer occurs in duodenal adenomas, the result of surgery is poor. We have performed prophylactic pancreaticoduodenal resection (PDR) for nonmalignant severe duodenal polyposis in five patients since 1991. No operative mortality was observed. One patient developed a pancreatic fistula which was successfully managed by medical treatment. The mean follow-up was 35 months. All five patients are still alive and have a good functional outcome. Prophylactic PDR may be indicated in familial adenomatous polyposis when duodenal polyposis is severe. Stages III and IV of Spigelman's classification, periampullary adenoma, age above 40, and family history of duodenal cancer are factors that may lead to the decision to perform prophylactic PDR.

Adenoma↗
PubMed1991

Value of combined phenotypic markers in identifying inheritance of familial adenomatous polyposis.

Familial adenomatous polyposis is an autosomal dominant disease characterised by the development of hundreds of colorectal adenomas in young adults. Occult radio-opaque jaw lesions and pigmented ocular fundus lesions (formerly called congenital hypertrophy of the retinal pigment epithelium) are extraintestinal phenotypic markers for this disorder. We evaluated the usefulness of the combination of these markers for identifying patients who have inherited familial adenomatous polyposis. Forty three affected patients and 12 unaffected first degree relatives from 24 families with familial adenomatous polyposis, including four families without extraintestinal manifestations, were examined for both phenotypic markers. Thirty three of the 43 patients (77%) with familial adenomatous polyposis were positive for both markers, including patients from two families without extraintestinal manifestations. By contrast, only one of 12 (8%) unaffected first degree relatives over 35 years of age had both markers. The sensitivity of the combination of these markers in identifying patients who inherited familial adenomatous polyposis was 77%, the specificity 92%, the predictive value of a positive test 97%, the predictive value of a negative test 52%, and the efficacy 80%. The combined markers had improved efficacy over either marker alone (70% for occult radio-opaque jaw lesions and 67% for pigmented ocular fundus lesions). We conclude that the presence of both occult radio-opaque jaw lesions and pigmented ocular fundus lesions in a person at risk indicates a high probability of inheritance and expression of familial adenomatous polyposis.

Adenomatous Polyposis Coli↗
PubMed1996

Clinical findings in a family with familial adenomatous polyposis and a missense mutation of the adenomatous polyposis coli gene.

BACKGROUND: More than 100 different mutations in the adenomatous polyposis coli (APC) gene have been identified; virtually all lead to the production of a truncated protein. Clinical details of patients with missense mutations undoubtedly cosegregating with the disease have not been reported and may be relevant in understanding the APC protein function. METHODS: In one family with familial adenomatous polyposis (FAP) the APC gene was analyzed by SSCP and sequencing of the aberrant SSCP band. RESULTS: A missense mutation in exon 15 at nucleotide 4921 segregating with the disease was observed. This predicts a tryptophan instead of an arginine at amino acid 1641 of the APC protein. No such mutation was present in 100 control subjects. CONCLUSIONS: In this family the colonic manifestations are as expected for classical FAP. However, the occurrence of congenital hypertrophy of the retinal pigment epithelium is unusual, owing to the inconsistency of this manifestation between family members and because congenital hypertrophy of the retinal pigment epithelium is generally absent when mutations are after codon 1387.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Management of advanced duodenal polyposis in familial adenomatous polyposis.

Patients with familial adenomatous polyposis (FAP) are at increased risk for the development of periampullary cancer. The aim of this study was to evaluate the roles of endoscopic and surgical therapy in the management of advanced duodenal polyposis in FAP. From 1990 to 1995, seventy-four FAP patients were enrolled in a prospective endoscopic surveillance protocol. Among these, 11 (14.8%) developed advanced duodenal polyposis and one had duodenal adenocarcinoma. Six patients underwent endoscopic resection of duodenal (n=5) or ampullary adenomas (n=1). The following operations were performed in the remaining six patients: ampullectomy in four, open polypectomy in one, and a Whipple procedure in one. There was one patient who died of acute pancreatitis following endoscopic ampullectomy. The patient with invasive duodenal cancer died of local recurrence. Small polyps were observed at the site of previous resection in all (9 of 9) patients undergoing repeat endoscopy during a mean follow-up of 18 months (range 4 to 34 months). An endoscopic and local surgical resectional approach to advanced duodenal polyposis in FAP is fraught with high recurrence rates, although recurrent polyps are small and may be amenable to retreatment in the future. Long-term follow-up is necessary to prove that deaths from duodenal or ampullary cancer are prevented with this strategy.

Adenomatous Polyposis Coli↗
PubMed1998

Surgical treatment of severe duodenal polyposis in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are at risk for adenomas and cancers in the duodenum but the ideal management of duodenal polyposis remains uncertain. METHODS: The outcome of surgical resection was analysed in 18 patients with FAP who had severe duodenal polyposis. RESULTS: Duodenotomy and clearance of duodenal adenomas was performed seven times in six patients. There were two duodenal leaks and, after a mean follow-up of 53 (range 36-72) months, duodenal adenomas recurred in all patients and five had severe polyposis. Pancreatoduodenectomy was performed in seven patients with severe duodenal polyposis. Histology of the specimens revealed two unsuspected duodenal carcinomas at an early stage. After a mean follow-up of 42 months all patients were alive and well, and there was no case of jejunal polyposis. Pancreatoduodenectomy was attempted in five patients with duodenal cancer and only one survived more than 4 years. CONCLUSION: Surgical excision of duodenal adenomas should be discussed before carcinoma occurs. Surgical polypectomy fails to guarantee a polyp-free duodenum and carries a risk of postoperative complications whereas pancreatoduodenectomy eliminates the risk of duodenal cancer with an acceptable morbidity rate. Pancreatoduodenectomy could be offered to some patients with large or multiple villous duodenal adenomas repeatedly showing severe dysplasia.

Adenoma↗