Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation

BACKGROUND: Serrated adenoma is a precursor of colorectal cancer. AIM: To clarify possible genotype-phenotype correlations of serrated adenomas in familial adenomatous polyposis (FAP). Patients: Eleven patients from eight families with FAP. METHODS: We performed total colonoscopy with multiple biopsies in patients. Neoplasia with a serrated glandular structure was regarded as a serrated adenoma. In each patient, germline mutations of the APC gene were determined. Colonic phenotype was compared with germline mutations of the APC gene. RESULTS: Serrated adenomas were found in three patients. These patients had macroscopic polyps <100 in number. Pedigrees with serrated adenomas had the truncating germline APC mutation at codon 161, 332, or 1556 while in the other pedigrees mutations were found between codons 554 and 1324. CONCLUSIONS: In FAP, serrated adenoma may be a phenotype characteristic of the attenuated form.     

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

Background—Familial adenomatouspolyposis usually results in colonic polyposis with hundredsto thousands of polyps, congenital hypertrophy of the retinal pigmentepithelium (CHRPE), and variable extracolonic features. Recent reportsindicate that patients with distal mutations between codons 1445 and1578 do not express CHRPE and have a high incidence of desmoid tumours.
Patients—The family studied has an unusualphenotype of sparse colonic polyposis but profuse uppergastrointestinal polyposis. Affected subjects do not have CHRPE.
Methods—The protein truncation testfollowed 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 sparsecolonic polyposis but severe upper tract polyposis may be associatedwith mutations between codons 1445 and 1578.
Conclusions—Study of duodenal and colonic polypsin further cases with mutations in this region is warranted. Suchmutations may preferentially cause duodenal adenomas and desmoidtumours as somatic mutations in these tumours also occur in thisregion, unlike colorectal tumours where somatic mutations occur moreproximally. This study emphasises the importance of screening the uppergastrointestinal tract even when the colonic disease is mild.

Keywords:familial adenomatous polyposis; duodenal polyps; APCmutations; colorectal polyps

     

Variation of a variation: case report of attenuated familial adenomatous polyposis

BACKGROUND: First described in 1988, attenuated familial adenomatous polyposis (AFAP) is a rare autosomal dominant precancerous condition of the gastrointestinal tract. Few reports have described adenocarcinomatous change in the gastroduodenal region thus far. CASE OUTLINE: We report a case of AFAP presenting with extensive gastric polyposis and ampullary adenocarcinoma in absence of a positive family history of gastrointestinal cancer and a novel mutation.     

Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes.

The APC gene is mutated in the germline of people from families where there is a predisposition to develop polyposis coli. Many mutations have been described but the relation between their site and the phenotypic expression of the disease remains unclear. The most commonly seen mutation occurs at codon 1309. Many other mutations have been described towards the 5' end of exon 15 of the APC gene but comparatively few have been seen towards the 3' end. Recent reports have indicated the possibility of a functional boundary with respect to severity and age of onset of disease, which lies towards the 5' end of the gene. This report describes a large family whose affected members present with a very variable phenotype ranging from an early onset and severe form to a comparatively mild later onset one. The mutation that predisposes to disease in this family is at a previously undescribed site that lies towards the 3' end of exon 15 of the APC gene, which results in a stop codon. Interestingly, the stop codon is 63 codons downstream of the mutation and therefore may affect the expression of the disease. The addition of this mutation to the growing list of mutations described in the APC gene may provide some insight into the genotype/phenotype relation of the disease thus contributing to the understanding and significance of mutations at specific sites in the APC gene.     

Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study

BACKGROUND & AIMS: Management of patients with familial adenomatous polyposis (FAP) can consist of colectomy with ileorectal anastomosis (IRA). Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of colorectal adenomas in the retained rectal segment of FAP patients, although long-term use of this therapy has not been studied. We evaluated the long-term effectiveness and toxicity of sulindac in attempting to maintain retained rectal segments free of adenomas. METHODS: Twelve FAP patients (5 women), mean age 37.1 years, with IRA received sulindac (mean dosage, 158 mg/day) for a mean period of 63.4 +/- 31.3 months (range, 14-98 months). Number, size, and histologic grade of polyps, side effects, and medication compliance were assessed every 4 months. RESULTS: Seven of 12 patients (58%) remained in the study (6 of these polyp-free) for a mean of 76.9 +/- 27.5 months. Five of 12 patients (42%) withdrew from the trial after a mean follow-up period of 44 +/- 28 months (range, 14-89 months). A significant regression of polyp number was observed in all patients at 12 months (P = 0.039) and at a mean of 63.4 +/- 31.3 months (P = 0.006). Prevention of recurrence of higher-grade adenomas (tubulovillous, villous adenomas) was also observed (P = 0.004). At 35 months of follow-up, 1 patient developed stage III cancer in the rectal stump. The most common side effect was rectal mucosal erosions in 6 patients. CONCLUSIONS: Long-term use of sulindac seems to be effective in reducing polyp number and preventing recurrence of higher-grade adenomas in the retained rectal segment of most FAP patients. Erosions at the IRA site can preclude adequate dose maintenance.     

Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation

Background: Many patients with familial adenomatous polyposis (FAP) die from desmoid tumours which can arise spontaneously but often appear to be surgically induced by prophylactic colectomy. FAP results from germline adenomatous polyposis coli (APC) gene mutations and desmoids arise following biallelic APC mutation, with one change usually occurring distal to the second β-catenin binding/degradation repeat of the gene (3′ to codon 1399). We have suggested that because families with germline mutations in this region already have the requisite change, they are more likely to develop desmoids. However, there are families with 5′ germline mutations where desmoids are common.     

Novel germline APC mutations in Swedish patients with familial adenomatous polyposis and Gardner syndrome

BACKGROUND: Familial adenomatous polyposis (FAP) is a familial cancer syndrome in which affected individuals develop multiple adenomatous polyps and are thereby at greatly increased risk of developing colorectal cancer. Gardner syndrome is a variant of FAP, in which the patients also develop extraintestinal tumors, in particular osteomas and desmoid tumors. An attenuated form of the disease (AFAP) is associated with fewer polyps, but still a high risk for colorectal cancer. Germline mutations in the adenomatosis polyposis coli (APC) gene cause FAP and Gardner syndrome and have recently been associated also with the development of AFAP. METHODS: We have analysed the entire APC gene for germline mutations in 7 patients with FAP and in 6 patients with suspected AFAP. Mutation screening was performed by direct sequencing of exons 1-14 and using the protein truncation test for analysis of exon 15. RESULTS: Novel disease-causing germline mutations, all of which resulted in truncation of the APC protein, were identified in 6 of the 7 patients with FAP or Gardner syndrome. No APC mutation was detected in any of the 6 patients with suspected AFAP. CONCLUSIONS: This study reports novel FAP- and Gardner syndrome-causing mutations in the APC gene. The lack of APC mutations in patients with multiple polyps at young age indicates that other genetic defects may cause this phenotype.     

Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16 clinical manifestations were analysed according to the patient's mutational status. Two sided independent t sample test, two sided chi(2) test, and odds ratios were calculated. RESULTS: Patients without identified APC mutations had a unique and severe phenotype, which was roughly described as: young age at diagnosis and subsequent death in spite of development of few colorectal adenomas; low risk of involvement of the upper gastrointestinal tract, as reflected by a low mean Spigelman stage, and a low risk of fundic gland polyposis. Finally, they had significantly fewer affected family members, although they do not themselves more often represent an isolated case. CONCLUSIONS: The severe phenotype should be considered when counselling FAP families in which attenuated FAP is excluded and in which a causative APC mutation has not been identified.     

A case of attenuated familial adenomatous polyposis coli (AFAP)

We describe an asymptomatic female patient who was diagnosed with multiple tubular and tubulovillous adenomas in the right-sided colon on routine colonoscopy at the age of 59 years. Genetic testing identified a germline truncating mutation at codon 405 (R405X) of the adenomatous polyposis coli (APC) gene. This mutation is located in the alternatively spliced region of exon 9, a region that is associated with an attenuated phenotype of familial adenomatous polyposis (AFAP). To our knowledge this report describes for the first time the R405X germline mutation in association with AFAP. Our patient had no extracolonic manifestations of AFAP. Treatment consisted of a right hemicolectomy with ileotransversal anastomosis plus complete endoscopic polypectomy in the left-sided colon. AFAP is a poorly defined condition with unknown prevalence and penetrance that requires individual therapy and life-long surveillance. Because of marked intrafamilial phenotypic variance, it is crucial to identify these patients and implement proper endoscopic surveillance at an early age in family members carrying this mutation.     

Desmoid tumor of mesentery in familial adenomatous polyposis: a case report

Our case concerns a 52-year-old male with FAP, who was treated surgically by restorative colectomy and ileal pouch anal anastomosis. Three years later, he presented with acute epigastric pain and obstructive ileum. While a mass in the left lateral abdominal region was palpated. The patient underwent laparotomy, some adhesions were dissected and biopsies were taken from the mass. Pathological examination revealed a desmoid tumor of the mesentery.     

About a case of familial adenomatous polyposis

The authors present a case of FAP, familial adenomatous polyposis. This condition comprises 3 different syndromes characterized by the development of numerous polyps in the colon. Other different expressions of the same genetic anomaly are: familial adenomatous polyposis coli, Gardner's syndrome and Turcot's syndrome. The main risk for these pathologies consists in the frequent cancer outcome, which usually occurs between the 4th and the 5th decade of life and, however, after about 12 years from the first diagnosis. The patient came to the authors' observation in the surgery room of the department of geriatrics, in the university of Catania, where patients from South Italy and Sicily are treated. He had a severe anemic condition and poor general health. At the time of the diagnosis the patient, 56 years old, was subjected to endoscopic investigations which showed extensive polyposis of the entire colon and of the stomach, later on typified as 'Familial polyposis'. He was then subjected to total colectomy and gastric polypectomy. Besides, the patient and his direct family members (4 children and 2 sisters) were also genetically screened. The results proved that the patient and 3 of his children presented a genetic mutation located in connection with one of the two alleles of the APC gene. The potentially cancerous evolution makes it necessary to perform a genetic screening of all direct relatives of patients affected by FAP in order to both uncover the genetic anomaly responsible for this pathology and to prevent cancer, which is the natural outcome of this disease.     

A family with attenuated familial adenomatous polyposis identified because of fundic gland polyposis

We report a 41-year-old woman who had fundic gland polyposis without a colorectal polyp. Because her father had colon cancer, multiple colorectal polyps and the gastric polyposis, we suspected AFAP and researched the APC gene. There was 1 base pair deletion of guanine at codon 99-100 in exon 3 of the APC gene, and its frame shift mutation made stop codon at codon 124. It was proved that the gene carrier of AFAP can be discovered based on the family-history and the presence of fundic gland polyposis, even when no colorectal polyps exist.     

Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis

PURPOSE: Familial adenomatous polyposis is an inherited colorectal cancer syndrome characterized by the presence of multiple adenomatous colorectal polyps. Molecular studies have revealed that germline mutations in the APC gene are the underlying cause of the disease. The nonsteroidal anti-inflammatory agent sulindac has been shown to reduce the number of colorectal adenomas. Most sulindac trials in the large bowel have focused on the distal colon and relatively little is known about its effect on the proximal colon. Moreover, it is unknown whether the site of the APC mutation affects the efficacy of sulindac. METHODS: This study investigated whether there were regional differences in the effect of sulindac on the colon and whether response to sulindac was dependent on the site of mutation in the APC gene. In an open prospective study 17 patients with familial adenomatous polyposis were treated with 300 mg oral sulindac daily for four months followed by a washout phase of six months. Ten of the patients had an intact colon and seven had rectal stumps only. The number, size, and the degree of dysplasia of the adenomas were evaluated by colonoscopy at entry, end of treatment and end of the study. RESULTS: Overall, a statistically significant decrease in the number of adenomas was observed (120 +/- 112 to 28 +/- 64, P = 0.007). After cessation of sulindac treatment the number of adenomas increased to 48 +/- 44.5, but remained significantly lower than the values observed at baseline. In the ten patients with intact colons, adenomas decreased by sevenfold in the proximal colon (103 +/- 73 to 15.1 +/- 47.4, P = 0.011) and twofold in the distal colon (80 +/- 52 to 29.6 +/- 37.2, P = 0.005). The size of adenomas and the grade of dysplasia also decreased. No correlation could be seen between the APC mutation site and the response to treatment. CONCLUSION: These data indicate that sulindac reduces the number of adenomas in the entire colon and that the effect seems to be more pronounced in the proximal colon.     

Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9

BACKGROUND: The phenotypic spectrum of familial adenomatous polyposis (FAP) varies from the classic appearance of hundreds of adenomatous colonic polyps in the young adult and early onset colorectal cancer, to the occurrence of sparse adenomas in the older adult, "attenuated" FAP, due to mutations at the 5' or 3' ends of the APC gene. AIMS: To investigate marked intrafamilial phenotypic variation occurring in a family with an APC gene mutation in exon 9. PATIENTS: An extended kindred of 22 people of whom 16 had colorectal neoplasia and/or were APC mutation carriers. RESULTS: Phenotypic manifestation varied from classic FAP to a complete lack of clinical or endoscopic, or bioptic disease in five people in three different generations. This occurred in four of them over two generations, in spite of having a confirmed 11 bp insertion causing a frame shift and stop codon (363) in exon 9 of the APC gene. CONCLUSIONS: At present, it is assumed that in this family there is alternative splicing of the APC gene, and/or unidentified modifying genetic factors. The family illustrates the importance of genetic testing in evaluating carrier status and not just clinical examination. This clinical observation also high- lights the dilemma in recognising the possible contribution of low penetrance germline APC mutations to what has been considered "sporadic" colorectal neoplasia.     

Effect of the non-steroidal anti-inflammatory drug sulindac on colorectal adenomas of uncolectomized familial adenomatous polyposis

Background: The aim of the present study was to elucidate the effect of sulindac on uncolectomized familial adenomatous polyposis (FAP). Methods: Seven FAP patients (SU group) without proctocolectomy were given sulindac 300 mg/day orally for 12 months. Six FAP patients without sulindac (non‐SU group) served as controls. Colorectal lesions were assessed by protrusion index (no. radiolucent areas/cm²; PI) under barium enema examination and non‐polypoid lesion were assessed under chromoscopy prior to and at the end of the observation period. In the SU group, germline adenomatous polyposis coli (APC) mutation was determined by protein truncation test. Results: In the SU group, PI decreased significantly in the distal colon (from 3.0 ± 1.1 to 1.1 ± 0.8/cm², P < 0.02) and in the proximal colon (from 3.4 ± 2.4 to 0.9 ± 1.3/cm², P < 0.02). The PI in the non‐SU group slightly but significantly increased in the distal colon (from 1.0 ± 0.8 to 1.2 ± 0.9/cm²; P < 0.05) and it remained unchanged in the proximal colon (from 0.6 ± 0.3 to 0.7 ± 0.3/cm²; P > 0.05). Chromoscopy at the end of observation identified non‐polypoid lesions in five patients in the SU group, whereas such lesions were not found in the non‐SU group (71% vs 0%, P = 0.016). Decrease in PI was not different among distal APC mutation (exons 1–9), proximal APC mutation (exons 10–15) and negative mutation. Conclusion: Sulindac reduces colorectal adenomas of protruding type in uncolectomized FAP. The effect of sulindac may be unrelated to genotype of FAP.     

Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis

BACKGROUND & AIMS: An attenuated form of familial adenomatous polyposis has been described, but the phenotype remains poorly understood. METHODS: We performed genetic testing on 810 individuals from 2 attenuated familial adenomatous polyposis kindreds harboring an identical germline adenomatous polyposis coli gene mutation. Colonoscopy was performed on mutation-positive persons. RESULTS: The disease-causing mutation was present in 184 individuals. Adenomatous polyps were present in 111 of 120 gene carriers who had colonoscopy at an average age of 41 years. The median number of adenomas was 25 (range, 0-470), with striking variability of polyp numbers and a proximal colonic predominance of polyps. Colorectal cancer occurred in 27 mutation carriers (average age, 58 years; range, 29-81 years), with 75% in the proximal colon. The cumulative risk of colorectal cancer by age 80 was estimated to be 69%. An average of 3.4 recurrent polyps (range, 0-29) were found in the postcolectomy rectal remnant over a mean of 7.8 years (range, 1-34 years), with 1 rectal cancer. CONCLUSIONS: This investigation shows that attenuated familial adenomatous polyposis in the kindreds examined shows a much smaller median number of polyps than typical familial adenomatous polyposis, a wide variability in polyp number even at older ages, and a more proximal colonic location of polyps and cancer, yet it is associated with an extremely high risk of colon cancer. The phenotype of attenuated familial adenomatous polyposis mimics typical familial adenomatous polyposis in some cases but in others is difficult to distinguish from sporadic adenomas and colorectal cancer, thus making genetic testing particularly important.