Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status

Background—Familial adenomatous polyposis(FAP) is a clinically well defined hereditary disease caused bygermline mutations within the adenomatous polyposis coli (APC) gene.Although several techniques are applied in the mutation analysis of FAPkindreds about 20-50% of cases remain unclear, with no APC mutationidentified (APC negative).
Aims—To delineate phenotypic differences betweenAPC positive and APC negative patients with respect to colonic andextracolonic disease in order to determine whether additionalmechanisms are involved in the pathogenesis of FAP.
Methods—The entire coding region of the APC genewas analysed using single stranded conformation polymorphism andprotein truncation tests in 50 Swiss FAP families with a total of 161affected individuals. Differences in phenotypic manifestation werestatistically evaluated by Student's t test, Fisher'sexact test, and χ² test.
Results—Thirty six families (72%) were APCpositive. Statistically significant differences between APC positiveand APC negative groups were found for the mean age at diagnosis ofcolonic polyposis (35.2 versus 45.3 years, respectively) and for theoccurrence of stomach polyps (14 patients, all APC positive).Additionally, APC negative patients displayed lower polyp numbers atdiagnosis and less extracolonic manifestations.
Conclusions—FAP kindreds without detected APCgene mutations present with a notably milder disease phenotype comparedwith APC positive families, suggesting that different genetic factors might be involved.

Keywords:familial adenomatous polyposis; adenomatouspolyposis coli gene; mutation; colorectal cancer; extracolonicmanifestations

     

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.     

Development of duodenal cancer in a patient with familial adenomatous polyposis

A Japanese woman with familial adenomatous polyposis in whom a duodenal ampullary adenoma underwent malignant change during a 10-year follow-up period is reported. After restorative proctocolectomy in 1989, and extensive small bowel resection for desmoid disease in 1991, regular surveillance duodenoscopies, including three to nine biopsies (mean, 4.8) were performed annually or biannually. Until 1995, the endoscopic findings of duodenal polyposis (including an ampullary polyp) did not progress and the histopathology did not worsen. In 1996, there was an increase in the number and size of the duodenal polyps, and the ampulla of Vater looked enlarged. Open surgery was discussed but not proceeded with because of the risk for short bowel syndrome. In January 1998, she was admitted with a diagnosis of acute pancreatitis. Duodenoscopy and radiological examination revealed that an advanced ampullary cancer had developed, and histopathology revealed a well-differentiated adenocarcinoma. Multiple hepatic metastases and ascites led to her death, in June, 1998. This in-vivo demonstration of the adenoma-carcinoma sequence highlights current limitations in the surveillance and treatment of duodenal lesions. Received: June 28, 1999/Accepted March 24, 2000     

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. Received: April 3, 2001 / Accepted: July 20, 2001     

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.     

Upper gastrointestinal neoplasia in familial polyposis

Upper gastrointestinal (UGI) endoscopy was performed in 41 asymptomatic American patients with familial polyposis to assess the prevalence of gastric and duodenal polyps and to characterize their pathological features. Eighteen patients (44%) had UGI endoscopic abnormalities. Six patients had both gastric and duodenal lesions. Eight patients had only gastric polyps, and four had duodenal polyps only. The presence of other extracolonic expressions of polyposis had a suggestive but statistically insignificant correlation with UGI polyps. Patients with familial polyposis and duodenal adenomatous polyps are at high risk for the development of periampullary cancer; screening and identification of these individuals is recommended.Supported in part by NIH grant CA-31711     

Hepatocellular adenoma in a male with familial adenomatous polyposis coli

Hepatocellular adenoma (HA) is a benign liver tumor most frequently occurring in young women using oral contraceptives. We report a rare case of HA in a 27-year-old male patient with familial adenomatous polyposis (FAP). The patient underwent a total colectomy and ileo-rectal anastomosis for FAP in 2003. A preoperative computed tomography scan of the abdomen disclosed a tumor in the left-lobe of the liver, 5.8 cm in diameter. Pathologic examination of a needle biopsy disclosed HA, but he had never used anabolic steroids or other known inducers of HA. The size of the liver mass gradually increased to 8.5 cm during a follow-up period of 38 months, and a left hepatectomy was performed in 2006. Pathology of the resected specimen confirmed the diagnosis of HA. Although FAP is known to be complicated with neoplasia in various extracolonic organs, only five reported cases of HA have developed in patients with FAP, including this case. This is the first report of HA to develop in a male FAP patient.     

High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis

BACKGROUND & AIMS: Inherited colorectal polyposis has been linked to constitutive mutations of the APC tumor suppressor gene. Recently, germline mutations in the base excision repair gene MYH have been associated with a recessively inherited form of the disease. The aim of this study was to evaluate germline mutation frequencies of both MYH and APC susceptibility genes in Italian patients with attenuated familial adenomatous polyposis. METHODS: The analysis was performed in 14 unrelated patients by using the protein truncation test for APC and genomic DNA sequencing for MYH. RESULTS: Overall, we identified 7 of 14 (50%) mutation carriers. Two patients were heterozygotes for an APC truncating mutation (2 of 14 [14%]), whereas 5 proved to be homozygotes or compound heterozygotes for MYH gene alterations (5 of 14 [36%]). Two MYH missense mutations, Y165C and G382D, already found to be frequent among patients from northern Europe, were also preponderant in our survey. Individuals with APC-associated syndrome showed a dominant family history of polyposis, whereas patients with MYH-associated disease were either apparently sporadic cases or had a family history consistent with recessive inheritance. MYH biallelic mutation carriers were up to 60% (5 of 8) among patients showing at least 30 adenomas and a family history with no vertical transmission of polyposis. CONCLUSIONS: On the basis of our data, patients with attenuated familial adenomatous polyposis with >30 adenomas and no obvious vertical transmission of the disease should be considered for MYH gene testing.     

Decision analysis in the surgical treatment of patients with familial adenomatous polyposis: a Dutch-Scandinavian collaborative study including 659 patients

BACKGROUND AND AIMS: The choice of colorectal surgery in patients with familial adenomatous polyposis lies between the morbidity of proctocolectomy and ileum-pouch-anal anastomosis (IPAA) and the mortality from rectal cancer after total colectomy and ileorectal anastomosis (IRA). The aims of the present study were: (1) to assess the risk of dying from rectal cancer after IRA, (2) to compare the life expectancy between patients with an IRA and those with an IPAA, and (3) to investigate whether regular endoscopic examination of the rectum leads to detection of cancer at an earlier stage. METHODS: Clinical and pathological data on 659 patients who underwent colectomy and ileorectal anastomosis were collected from four national polyposis registries-that is, in Denmark, Finland, Sweden, and the Netherlands. Data were analysed using survival analysis methods. Decision analysis was used to compare the life expectancy between patients with an IRA and those with an IPAA. RESULTS: A total of 47 patients developed rectal cancer after IRA. The risk of dying from rectal cancer was 12.5% (95% confidence interval 7.1--17.9%) by age 65. Compared with IRA, IPAA would lead to an increase in life expectancy of 1.8 years. Seventy five per cent of patients with rectal cancer had a negative rectoscopy within 12 months before the diagnosis. CONCLUSION: IRA is associated with substantial mortality due to rectal cancer. Follow up examinations of the rectum does not have sufficient preventive effect on morbidity and mortality of rectal cancer.     

Presence of c.3956delC mutation in familial adenomatous polyposis patients from Brazil

AIM: To characterize APC gene mutations and correlate them with patient phenotypes in individuals diagnosed with familial adenomatous polyposis(FAP) in northern Brazil. METHODS: A total of 15 individuals diagnosed with FAP from 5 different families from the north of Brazil were analyzed in this study. In addition to patients with histopathological diagnosis of FAP,family members who had not developed the disease were also tested in order to identify mutations and for possible genetic counseling. All analyzed patients or their guardians signed a consent form approved by the Research Ethics Committee of the Jo?o de Barros Barreto University Hospital(Belem,Brazil). DNA extracted from the peripheral blood of a member of each of the affected families was subjected to direct sequencing. The proband of each family was sequenced to identify germline mutations using the Ion Torrent platform. To validate the detected mutations,Sanger sequencing was also performed. The samples from all patients were also tested for the identification of mutations by real-time quantitative polymerase chain reaction using the amplification refractory mutation system. RESULTS: Through interviews with relatives and a search of medical records,it was possible to construct genograms for three of the five families included in the study. All 15 patients from the five families with FAP exhibited mutations in the APC gene,and all mutations were detected in exon 15 of the APC gene. In addition to the patients with a histological diagnosis of FAP,family members without disease symptoms showed the mutation in the APC gene. In the present study,we detected two of the three most frequent germline mutations in the literature: the mutation at codon 1309 and the mutation at codon 1061. The presence of c.3956 del C mutation was found in all families from this study,and suggests that this mutation was introduced in the population of the State of Pará through ancestor immigration(i.e.,a de novo mutation that arose in one member belonging to this state from Brazil). CONCLUSION: Regardless of its origin,the c.3956 del C mutation is a strong candidate biomarker of this hereditary cancer syndrome in families of northern Brazil.     

Pancreaticoduodenectomy for advanced duodenal and ampullary adenomatosis in familial adenomatous polyposis

Background

Patients with familial adenomatous polyposis (FAP) develop duodenal and ampullary polyps that may progress to malignancy via the adenoma–carcinoma sequence.

Objective

The aim of this study was to review a large series of FAP patients undergoing pancreaticoduodenectomy for advanced duodenal and ampullary polyposis.

Methods

A retrospective case notes review of all FAP patients undergoing pancreaticoduodenectomy for advanced duodenal and ampullary adenomatosis was performed.

Results

Between October 1993 and January 2010, 38 FAP patients underwent pancreaticoduodenectomy for advanced duodenal and ampullary polyps. Complications occurred in 29 patients and perioperative mortality in two. Postoperative histology revealed five patients to have preoperatively undetected cancer (R = 0.518, P < 0.001).

Conclusions

Pancreaticoduodenectomy in FAP is associated with significant morbidity, but low mortality. All patients under consideration for operative intervention require careful preoperative counselling and optimization.     

Variability in the severity of colonic disease in familial adenomatous polyposis results from differences in tumour initiation rather than progression and depends relatively little on patient age

INTRODUCTION: As large scale genetic analysis becomes increasingly efficient, attention is turning to problems arising from inaccurate measurement of the phenotype. We have investigated the underlying basis of variation in disease severity in the large intestine of familial adenomatous polyposis (FAP) patients. The development of objective and reproducible measures may have future use in genetic studies, such as analysis of modifier genes. METHODS: We examined the ratio of adenomas to crypts from microscopic slides taken from all parts of the colon of 44 resected FAP specimens. These findings were compared with a carefully reported macroscopic polyp count. Age dependency of adenoma counts (in the period around colectomy) was also analysed. RESULTS: The adenoma:crypt ratio strongly correlated with reported macroscopic polyp count (r=0.82, p<0.001) with no significant residual variation. Polyp density measured using the adenoma: crypt ratio did not vary significantly within an individual colon. Apparent visible variation in polyp density within any colon was not found at the microscopic level. There was no detectable age related increase in macroscopic adenoma count between siblings over the age range at which colectomies were performed. DISCUSSION: The severity of colonic polyposis in FAP can be determined accurately by counting the adenoma:crypt ratio in sections derived from stored tissue blocks. Variation between patients-dependent on APC genotype and, probably, modifier genes-is manifest at both the microscopic and macroscopic levels. Thus variation in disease severity is more likely to result from different rates of tumour initiation than from differences in progression of microadenomas to macroscopic tumours. The absence of a detectable relationship between adenoma number and age (over the range studied) suggests that most tumours may be initiated relatively early in the patient's life, perhaps at a time of particular susceptibility.     

Pancreatic acinar cell carcinoma in familial adenomatous polyposis

Pancreatic carcinoma is rarely associated with familial adenomatous polyposis (FAP). Ten patients with this association have been reported in the literature. However, detailed data were available in only a few cases. The first case of pancreatic acinar cell carcinoma associated with FAP is reported. A 51-year-old man who had undergone total colectomy and ileoproctostomy for colonic polyposis 29 years previously was admitted with a cancer in the residual rectum. Preoperative examinations revealed a tumor in the head of the pancreas. Pancreaticoduodenectomy and very low anterior resection of the rectum were performed. Histologically, the tumor of the pancreas was acinar cell carcinoma. In patients with FAP, we recommend careful surveillance of not only the gastrointestinal tract but also of other organs such as those of the pancreaticobiliary system and the endocrine organs.     

Prednisolone therapy for intra-abdominal desmoid tumors in a patient with familial adenomatous polyposis

The management of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis (FAP) is very difficult. Non-steroidal anti-inflammatory drugs (NSAIDs), anti-estrogenic agents, and steroids are most commonly used, because surgical removal of these tumors may result in severe morbidity, with local recurrence being common. We report a patient with FAP and intra-abdominal desmoid tumors that regressed markedly after prednisolone therapy. The patient, a 38-year-old woman, had undergone total colectomy and ileorectal anastomosis with a diagnosis of FAP with colon cancer. Approximately 17 months after the surgery, she noticed an elastic firm lump in the abdominal wall. She also experienced lower abdominal distension. Computed tomography (CT) of the lower abdomen showed an invasive heterogenous low-density mass occupying the intra-abdominal space. She was treated with sulindac, NSAID, at 300 mg/day, the diagnosis being intra-abdominal desmoid tumors. She exhibited an intestinal obstruction about 9 months after the initiation of sulindac therapy. We changed the treatment and began prednisolone (initial dose, 40 mg/day). This treatment was continued for two years; subsequently the lesions regressed markedly. She is currently well, more than 3 years after the withdrawal of prednisolone.     

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.     

APC gene mutations in Chinese familial adenomatous polyposis patients

AIM:To study the characteristics of APC(adenomatous polyposis coli)gene germline mutation in Chinese patients with familial adenomatous polyposis(FAP).METHODS:APC gene from 14 FAP families was amplified by polymerase chain reaction(PCR)and underwent direct sequencing to determine the micromutation type.For the samples without micromutation,the large fragment deletion of APC gene was examined by multiplex ligation-dependent probe amplification(MLPA).RESULTS:There were gene micromutations in 9 families with a...