Mutations In Adenomatous Polyposis Coli Gene Research Articles

Germinoma presenting as a fourth cranial nerve palsy in a patient with adenomatous polyposis coli ( APC) gene mutation

A 17-year-old boy with adenomatous polyposis and a history of an adenomatous polyposis coli (APC) gene mutation (IVS13(-2) A>G) presented for evaluation of vertical, binocular diplopia. Examination was suggestive of a fourth (trochlear) nerve palsy. A history of headaches was elicited and led to further investigation with neuroimaging, which identified a germinoma in the tectal plate and secondary hydrocephalus. We report the clinical, radiological, and histopathological findings of this patient, who to our knowledge is the first reported case of a germinoma occurring in association with adenomatous polyposis.

Familial Adenomatous Polyposis in Children and Adolescents

Familial adenomatous polyposis (FAP) is the most common inherited polyposis syndrome characterized by the development of hundreds of colorectal adenomatous polyps. The aim of this study was to review cases of FAP diagnosed at The Children's Hospital of Philadelphia in a 16-year period. Medical records of patients diagnosed as having FAP between 1990 and 2005 were reviewed. The collected data included disease presentation, genetic profile, extraintestinal manifestations, surveillance, and treatment. We identified 12 patients with FAP. The age range at presentation was 7 to 18 years. Seven (68%) patients presented due to symptoms, the most common of which was rectal bleeding (6 patients, 86%). The youngest age at which polyps were detected was 7 years. Eight patients (67%) had positive family history. Three patients had Gardner syndrome and 1 presented in infancy with hepatoblastoma. Four patients had adenomatous polyposis coli gene mutation identified. One patient was diagnosed as having rectal carcinoma in situ. Six patients (50%) had gastric fundic gland polyposis and 6 had duodenal adenomatous changes. Capsule endoscopy was performed in 3 patients; 1 had multiple polyps in the duodenum and the jejunum. Seven patients (58%) underwent total colectomy with no serious complications. FAP is a rare condition but with significant risk of cancer and comorbidity. In this series, patients commonly presented to medical attention due to their symptoms. The youngest patient with polyps detected was 7 years old. We identified 1 patient with rectal cancer in situ and high proportion of patients with duodenal adenomatous lesions. Majority of patients underwent early colectomy.

Rectum-Sparing Surgery May be Appropriate for Biallelic MutYH-Associated Polyposis

The risk of cancer or severe polyposis of the rectal stump after total colectomy for MutYH-associated polyposis is scarcely defined. To evaluate this risk, we describe the findings of endoscopic surveillance of the rectal stump in a series of patients with biallelic MutYH mutations and polyposis. This is a retrospective, observational, multicenter case series derived from 2 familial cancer registries. Biallelic, germ-line MutYH mutations were found in 14 patients with no adenomatous polyposis coli gene mutations. Eleven of them underwent total colectomy with ileorectal anastomosis and yearly proctoscopic surveillance thereafter. Phenotype and histology of rectal polyps were recorded at diagnosis and during follow-up. Development of adenomas and carcinomas during endoscopic surveillance of the rectal stump was observed. At diagnosis, 6 patients had attenuated polyposis (10-100 adenomas), 5 patients had classical polyposis, 8 patients had colon carcinoma, and no patient had rectal carcinoma. The mean number of rectal polyps at diagnosis was 2.64 ± 2.11 (range, 0-6). No patients had rectal cancer. The most frequent MutYH mutations were Y165C/Y165C and G382D/G382D in 6 and 2 patients, respectively. During surveillance of the rectal stump after surgery (median duration, 5 y; range, 2-23 y), no patient developed rectal cancer. The mean number of adenomas per proctoscopy was 1.23 ± 2.19 (range, 0-10 adenomas per proctoscopy). This study was limited by the small size and retrospective nature of the case series. Total colectomy with ileorectal anastomosis may be appropriate for patients with MutYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.

Apc MIN modulation of vitamin D secosteroid growth control

A central paradox of vitamin D biology is that 1alpha,25-(OH)(2) D(3) exposure inversely relates to colorectal cancer (CRC) risk despite a capacity for activation of both pro- and anti-oncogenic mediators including osteopontin (OPN)/CD44 and E-cadherin, respectively. Most sporadic CRCs arise from adenomatous polyposis coli (APC) gene mutation but understanding of its effects on vitamin D growth control is limited. Here we investigate effects of the Apc(Min/+) genotype on 1alpha,25-(OH)(2) D(3) regulation of OPN/CD44/E-cadherin signalling and intestinal tumourigenesis, in vivo. In untreated Apc(Min/+) versus Apc(+/+) intestines, expression levels of OPN and its CD44 receptor were increased, whereas E-cadherin tumour suppressor signalling was attenuated. Treatment by 1alpha,25-(OH)(2) D(3) or rationally designed analogues (QW or BTW) enhanced OPN but inhibited expression of CD44, the OPN receptor implicated in cell growth. These treatments also enhanced E-cadherin tumour suppressor activity, characterized by inhibition of beta-catenin nuclear localization, T-cell factor 1 and c-myelocytomatosis protein expression in Apc(Min/+) intestine. All secosteroids suppressed Apc(Min/+)-driven tumourigenesis although QW and BTW had lower calcium-related toxicity. Taken together, these data indicate that the Apc(Min/+) genotype modulates vitamin D secosteroid actions to promote functional predominance of E-cadherin tumour suppressor activity within antagonistic molecular networks. APC heterozygosity may promote favourable tissue- or tumour-specific conditions for growth control by vitamin D secosteroid treatment.

Spindles losing their bearings: Does disruption of orientation in stem cells predict the onset of cancer?

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an anti-tumourigenic mechanism. We describe how hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers.

Familial adenomatous polyposis and hypertension

In October, 2008, a 36-year-old man was referred to our unit with new onset of hypertension and adrenal hyperplasia. He had been diagnosed with familial adenomatous polyposis (FAP) in childhood, and had undergone a total colectomy at the age of 17 years. He had been under endoscopic surveillance since, with a recent polyp count of 50–60 (March). The next month, as part of his routine FAP screening programme, he had an abdominal CT scan, which showed bilateral macronodular adrenal hyperplasia. The largest nodule measured 4 cm by 2 cm on the right and 2·7 cm by 2·9 cm on the left (fi gure). On assessment in our unit, the patient was hypertensive at 150/100 mm Hg on lisinopril and amlodipine. Examination showed no clinical features suggestive of Cushing’s syndrome. Serum potassium concentration was normal at 3·8 mmol/L. Other biochemical investi gations excluded Cushing’s syndrome and phaeo chromocytoma. With confounding antihypertensive medications discontinued, plasma aldosterone measured 590 pmol/L, plasma renin activity (PRA) 0·2 pmol/mL·h, giving a ratio of aldosterone to PRA of 2950 (>2000 is highly suggestive of primary hyperaldosteronism). Saline infusion did not suppress aldosterone to below 280 pmol/L, further supporting this diagnosis. Selective adrenal vein sampling showed that the cortisol-corrected aldosterone ratio in the left adrenal vein was 3·05 (dominant) compared with a ratio of 0·74 in the right adrenal vein (non-dominant), with a ratio of 0·80 in the low inferior vena cava (peripheral). The dominant to non-dominant ratio at 4·15 was above the recommended cut-off of 4·0 for diagnosing unilateral aldosterone hypersecretion with 95% sensitivity and 100% specifi city. Furthermore, the non-dominant to peripheral ratio of >1 confi rmed that autonomous secretion of aldosterone was confi ned to the left. There were no radiological features of the right adrenal mass suggesting malignancy, apart from its size. With the fi nding of dominant left-sided aldosterone secretion, we decided that the patient would benefi t from laproscopic left adrenalectomy. When last seen in March, 2010, he was awaiting surgery, delayed pending investigation into duodenal polyps, another manifestation of FAP. FAP is associated with many extra-intestinal manifestations. Adrenal gland enlargement is even more common in patients with FAP than would be expected from the ascertainment bias due to frequent abdominal imaging. In a series of 738 FAP patients, 14 (7·4%) were found to have adrenal enlargement, compared with 0·6–3·4% in the general population. Of these, two were hypertensive and surgical removal of cortisol-secreting tumours was necessary. In a study of 30 FAP patients with adrenal adenomas, 3 needed adrenalectomy: one for a phaeochromocytoma; one for a non-functioning, malignant tumour; and one for an enlarging, non-functioning, benign adenoma. Thus, the majority of adrenal tumours associated with FAP are non-functioning and no treat ment is needed unless they enlarge. Diagnosis of those rare cases that are associated with hormone hypersecretion is important, because they are surgically treatable. Our case report describes aldosterone-secreting adrenal enlargement in a hypertensive patient with FAP. Recently, an association between tumour-suppressor APC (adenomatous polyposis coli) gene mutations and hyperaldosteronism has been proposed. Mice heterozygous for a truncating APC mutation had higher aldosterone concentrations than controls, with corresponding increases in urinary potassium excretion, despite the presence of hypertension and plasma volume expansion. These fi ndings suggest a potential pathophysiological link between the causative APC mutation and hyper aldosteronism in FAP. All FAP patients with incidentally discovered adrenal masses should have regular blood pressure measurements and be screened for possible Cushing’s syndrome, Conn’s syndrome, and phaeo chromo cytoma.

Noncolonic cancer stem cells in bone marrow of colorectal cancer patients

To investigate whether preoperative noncolonic cancer stem cells in bone marrow (BM) of R0 colorectal cancer (CRC) patients are cancer cells and impact on liver metastases (LM) rates. Prospective data on continuous CRC patients were collected from five centres. Bone marrow aspirates, taken at laparotomy, were sent to a single lab. Noncolonic cancer stem cells were defined according to UICC. A quantity of 3 x 10(6) BM cells per patient was processed with monoclonal antibodies against cytokeratin 20. APC or p53 gene mutation and microsatellite instability (MSI) were assessed in primary tumours (PT) by single-strand conformation polymorphism. Noncolonic cancer stem cells in BM of PT mutation or MSI-positive patients were isolated with immunobeads coated with magnetically labelled anti-human epithelial antigen antibody and DNA-screened for mutations. Although 199 patients were enrolled, 162 patients were available for analysis. No patients were lost to follow-up. Twenty-five (2-170) noncolonic cancer stem cells were found in BM of 40 patients. Twenty-two patients developed LM at 36-month follow-up. Adenomatous polyposis coli (APC) or p53 gene mutation or MSI were identified in the PT of 78 patients. The same gene mutations or MSI were not found in noncolonic cancer stem cells of the BM of these patients. After adjustment, there was no significant effect of confounding factors. Noncolonic cancer stem cells in BM had no impact on LM rates, cancer-specific death rates, or all death rates. Preoperative noncolonic cancer stem cells in BM of R0 CRC patients were not cancer cells and had no impact on LM rates.

Dietary-induced ERβ upregulation counteracts intestinal neoplasia development in intact male Apc Min/+ mice

Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ERbeta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERbeta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ERbeta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERbeta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ERbeta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ERbeta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ERbeta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.

Hypermethylation of APC promoter 1A is associated with moderate activation of Wnt signalling pathway in a subset of colorectal serrated adenomas

The role of Wnt signalling pathway in serrated adenomas (SAs) remains to be identified. The aim of this study was to determine whether Wnt signalling plays a role in the pathogenesis of SAs, and to clarify the mechanism of Wnt signalling activation in SAs. This study investigated immunoreactivities of adenomatous polyposis coli (APC) and beta-catenin, mutations of APC and beta-catenin genes, methylation status of APC promoter 1A in 12 SAs, and compared the findings with normal colorectal mucosa, hyperplastic polyps, traditional adenomas (TAs) and colorectal cancers (CRCs). APC expression was moderately decreased in SAs. Cytoplasmic accumulation of beta-catenin was demonstrated in 41.7% (5/12) of SAs, but membranous immunoreactivity of beta-catenin was lost in only 8.3% (1/12) of SAs. No beta-catenin mutation was detected in any of 12 SAs, and only one SA was found to be positive for APC gene mutation. Complete methylation of APC promoter 1A was found in 41.7% (5/12) of SAs, but in no TAs or CRCs. Hypermethylation of APC promoter 1A, instead of mutations involving APC and beta-catenin, contributes to moderate activation of Wnt signalling in a subset of SAs.

Impact of group IVA cytosolic phospholipase A 2 gene polymorphisms on phenotypic features of patients with familial adenomatous polyposis

Group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) plays a key role in tumorigenesis via generating arachidonic acids as the substrate of cyclooxygenase. The aim of this study was to elucidate the possible associations between cPLA ( 2 )alpha gene polymorphisms and phenotypic features of patients with familial adenomatous polyposis (FAP). A tag single nucleotide polymorphisms (SNPs)-based genotype-phenotype association study of the cPLA ( 2 )alpha gene was conducted in 73 Japanese patients from 59 families with FAP. Based on the HapMap database, seven tag SNPs of the cPLA ( 2 )alpha gene were selected and genotyped by direct sequencing analysis. The genotype-phenotype association in relation to the adenomatous polyposis coli (APC) gene mutation was also assessed. The single SNP analysis showed that rs3820185 C allele [odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2-4.9] and rs127446200 GG genotype (OR, 10.9; 95%CI, 1.6-69.8), were more frequent in patients with gastric fundic gland polyposis (FGP) than in those without. Rs12749354 C allele was more frequently found in patients with small intestinal adenoma (OR, 7.0; 95% CI, 1.5-30.4; p = 0.008). This association was also significant when adjusted for covariates (age, sex, and APC mutation) in a logistic regression analysis (adjusted OR, 7.4; 95% CI, 1.2-64.2; p = 0.027). The cPLA ( 2 )alpha gene may be a possible disease modifier gene in FAP.

Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in Apc Min /+ mice with natural ligands

Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of beta-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent beta-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development in Apc(Min/+) mice. These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers.

Multiple Neoplasia in a 15-year-old Girl With Familial Adenomatous Polyposis

A 15-year-old girl with adenomatous polyposis coli gene (APC) mutation and brain tumor-polyposis syndrome developed an unusual succession of cervicocephalic tumors (medulloblastoma, meningeal low-grade myxoid tumor, and papillary thyroid carcinoma), at the age of 5, 9, and 15 years, respectively. We discuss the genetic profile of the thyroid tumor in which a large somatic deletion of APC gene was found and the physiopathology of thyroid carcinoma in patients with germline APC mutation. We also point out the uncommon phenotype in this young girl with early multiple neoplasias and the difficulties of management of such familial adenomatous polyposis patients with occurrence of extracolonic cancers that require the use of potential trigger agents as radiotherapy or chemotherapy.

Implication of Adenomatous Polyposis Coli and MUTYH Mutations in Familial Colorectal Polyposis

Familial adenomatous polyposis is an autosomal dominantly inherited syndrome characterized by hundreds or thousands of colorectal polyps and a high risk of colorectal cancer at a young age. Truncating germline mutations in the adenomatous polyposis coli gene are detected in approximately 80 percent of patients with classical familial adenomatous polyposis and in approximately 10 percent of the attenuated familial adenomatous polyposis patients. We investigated the adenomatous polyposis coli and MUTYH genes mutations in a well-characterized series of 25 unrelated Italian patients with familial adenomatous polyposis. We characterized the specific adenomatous polyposis coli gene mutation in 10 probands, and identified eight truncating mutations (4 novel and 4 known mutations) and two splicing mutations. One of these, a novel missense mutation in exon 15, activates an exonic splicing enhancer control sequence. Moreover, 11 MUTYH gene mutations have been identified in 7 patients without a dominant family history of polyposis. This study enlarges the genotype-phenotype correlations of familial adenomatous polyposis and suggests that messenger alterations could be responsible for a subset of familial adenomatous polyposis cases without germ-line adenomatous polyposis coli or MUTYH gene mutations. It also confirms that genotype-phenotype correlations in MUTYH-associated polyposis are very complex.

APC Mutation Spectra in Sporadic Colon Cancer Tissue among Korean

Purpose: APC (adenomatous polyposis coli) gene is one of the tumor-suppressor genes that acts in the early stages of cancer. Among general colon cancer patients, normal APC gene expression is deficient in 80%. It seems that APC is the most important gene in the development of colon cancer. This study was performed to analyze the mutation spectra of APC gene in sporadic colon cancer tissue from Korean patients with colon cancer. Methods: A total of 38 patients with sporadic colon cancer were enrolled. Colon cancer tissues were analyzed for the determination of APC gene mutation spectra by multiplex ligation-dependent probe amplification (MLPA) method using SALSA MLPA P403 APC kit (MRC-Holland, Amsterdam, NL). Results: APC gene mutations showing deletion/duplication in one or more exons were detected in 23 (60.5%) patients. Duplication in 13 patients (56.5%), duplication and deletion in 7 patients (30.4%), and deletion in 3 patients (13.1%) was detected. The incidence of APC gene mutation found in this study was highest in exon 3. From this study, no significant differences were observed with respect to clinicopathologic findings and the presence or absence of APC mutations. Conclusion: The frequency of APC gene mutation was about 61% in Korean patients with colon cancer, it showed concordance with the previous reports on the frequency of APC gene mutation from Caucasian patients with sporadic colon cancer. However, in contrast to these reports, the frequency of duplication disclosed much higher than those of western countries.

A Therapeutic Cancer Vaccine Targeting Carcinoembryonic Antigen in Intestinal Carcinomas

A genetic vaccine platform based on DNA electroporation (DNA-EP) and adenovirus (Ad) was used to generate immune response against human carcinoembryonic antigen (CEA) and antitumor effects in murine models with spontaneous tumors arising in an orthotopic location. CEA transgenic (CEA.Tg) mice treated with the carcinogen 1,2-dimethylhydrazine developed CEA-overexpressing tumors that resembled human sporadic colorectal cancer. APC1638N/CEA hybrid mice, generated by crossing mice carrying the adenomatous polyposis coli (Apc1638N) gene mutation with CEA.Tg mice, are representative of human familial polyposis and develop polyps that overexpress the antigen. In both models, the DNA-EP/Ad vaccine succeeded in breaking immune tolerance and achieved significant antitumor effects in therapeutic settings. Our data suggest that genetic vaccines targeting CEA may be feasible strategies against gut tumors that overexpress the antigen. In addition, these models are powerful systems for evaluating antigen-specific tumor immunity and assessing therapeutic vaccine strategies for human colorectal cancer.

Aberrant β-catenin expression and adenomatous polyposis coli gene mutation in ameloblastoma and odontogenic carcinoma

The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC (adenomatous polyposis coli), beta-catenin and Axin are frequently mutated in some primary human cancers. This study was conducted to clarify the relation of beta-catenin accumulation and the mutation of the CTNNB1 (beta-catenin) gene with the mutation of APC gene in the process of development of odontogenic tumors including ameloblastoma and odontogenic carcinoma (OC). beta-Catenin accumulation was examined by immunohistochemistry in formalin-fixed, paraffin-embedded samples of six ameloblastomas and eight OCs. We also performed a mutation analysis of CTNNB1 and APC to examine the cause of beta-catenin accumulation. All ameloblastoma cases and six out of eight (75%) OC cases exhibited beta-catenin accumulation in the nucleus. CTNNB1 mutation was only found in one OC case, whereas three of six (50%) ameloblastoma cases and two out of eight (25%) OC cases had APC mutations within the mutational cluster region. Our findings suggest that aberrant beta-catenin expression and APC missense mutation may play an important role for the pathogenesis of epithelial odontogenic tumors.

Mitochondrial Targeting of Adenomatous Polyposis Coli Protein Is Stimulated by Truncating Cancer Mutations: REGULATION OF Bcl-2 AND IMPLICATIONS FOR CELL SURVIVAL

The adenomatous polyposis coli (APC) protein tumor suppressor is mutated in the majority of colon cancers. Most APC gene mutations cause deletion of the C terminus and disrupt APC regulation of beta-catenin turnover, microtubule dynamics, and chromosome segregation. Truncated APC mutant peptides may also gain unique properties, not exhibited by wild-type APC, which contribute to tumor cell survival and proliferation. Here we report a differential subcellular localization pattern for wild-type and mutant APC. A pool of APC truncation mutants was detected at mitochondria by cellular fractionation and confocal microscopy. In contrast, wild-type APC located poorly at mitochondria. Similar results were observed for endogenous and stably induced forms of APC, with the shortest N-terminal mutant peptides (N750, N853, N1309, N1337) displaying the strongest mitochondrial staining. The knock down of mutant APC(N1337) in SW480 tumor cells caused an increase in apoptosis and mitochondrial membrane permeability, and this correlated with reduced Bcl-2 protein levels in mitochondrial fractions. Interestingly, the silencing of APC did not alter expression of beta-catenin or the apoptotic regulatory factors Bax, Bcl-xL, or survivin. APC formed a complex with Bcl-2 in mitochondrial fractions, and this may contribute to the APC-dependent regulation of Bcl-2. We propose that a subset of cancer mutations induce APC mitochondrial localization and that APC regulation of Bcl-2 at mitochondria may contribute to tumor cell survival.

Desmoid Tumors in a Dutch Cohort of Patients With Familial Adenomatous Polyposis

Desmoid tumors are a severe extracolonic manifestation in familial adenomatous polyposis (FAP). Identification of risk factors might be helpful in the management of FAP patients with such tumors. The aim of this study was to assess potential risk factors for the development of desmoids in a cohort of Dutch FAP patients. The medical records of 735 FAP patients were analyzed for the occurrence of desmoids. Relative risks and survival times were calculated to assess the influence of potential risk factors (female sex, family history, mutation site, abdominal surgery, and pregnancy) on desmoid development. Desmoid tumors were identified in 66 of the 735 patients (9%). The cumulative risk of developing desmoids was 14%. No correlation was found between specific adenomatous polyposis coli mutation sites and desmoid development. Patients with a positive family history for desmoids had a significant increased risk to develop this tumor (30% vs 6.7%, P < .001). No association was found between female sex or pregnancy and desmoid development. Most desmoid patients (95%) had undergone previous abdominal surgery. In a substantial proportion of patients with an ileorectal anastomosis, it was impossible to convert the ileorectal anastomosis to an ileal pouch-anal anastomosis as a result of desmoid development. A positive family history of desmoids is an evident risk factor for developing desmoids. Most desmoids develop after colectomy. No correlation was found between desmoids and the adenomatous polyposis coli gene mutation site, female sex, and pregnancy. Ileal pouch-anal anastomosis is the appropriate type of surgery in FAP patients with a positive family history for desmoids.

Familial Adenomatous Polyposis in Children Younger than Age Ten Years: A Multidisciplinary Clinic Experience

Children with familial adenomatous polyposis have a greater mortality and morbidity in the first decade of life compared with the general population. Some children with a more severe disease phenotype present early with colorectal adenomata and may require colectomy at an early age. We present our multidisciplinary clinic experience with familial adenomatous polyposis in children younger than age ten years at the time of presentation. A cross-sectional analysis was performed on all patients with suspected or confirmed familial adenomatous polyposis presenting in the first decade of life and followed by the multidisciplinary Pediatric Hereditary Polyposis Clinic at our institutions. Analysis included demographics, clinical presentation and course, gene mutation testing, endoscopic-histologic findings, and surgical outcome. Twenty-two children (11 males) presented with suspected or confirmed familial adenomatous polyposis. Two were discharged from follow-up after negative adenomatous polyposis coli gene mutation testing. The rest underwent annual hepatoblastoma surveillance through age ten years with negative findings. Twelve patients presented with symptoms: six had de novo familial adenomatous polyposis. Seven had gastrointestinal hemorrhage and went on to colonoscopy. Four patients with adenomatous polyposis coli gene mutation at codon 1309 were referred for colectomy before age ten years. Referral to colectomy was earlier in patients with 1309 mutation and with de novo familial adenomatous polyposis. Children with familial adenomatous polyposis younger than age ten years may present presymptomatically for disease surveillance. Familial adenomatous polyposis with adenomatous polyposis coli gene mutation at codon 1309 entails a risk of a more aggressive phenotype; early colectomy may be indicated in children harboring this gene mutation.

Capsule endoscopy is useful and safe for small-bowel surveillance in familial adenomatous polyposis

Duodenal cancer and ampullary cancer are major causes of death after a prophylactic colectomy in patients with familial adenomatous polyposis (FAP). Forward-viewing endoscopy and side-viewing endoscopy are recommended in patients with FAP for surveillance of periampullary and duodenal polyposis. The study of polyps distal to the duodenum in FAP is limited. A capsule endoscopy (CE) allows visualization of the mucosa of the entire small bowel. The objective was to detect whether CE has clinical value or any utility for the surveillance of small-bowel polyps in patients with FAP and to evaluate whether there are genotypic factors that predict which patients are at a lower risk of small-bowel polyps. Two Italian tertiary-referral centers. Twenty-three patients with FAP who presented for a CE. Patients with FAP were examined by CE to assess the location, size, and number of small-bowel polyps. Patient age at CE, sex, years of observation after surgery, type of surgery, duodenal adenomas, and colorectal cancer at surgery were analyzed. All patients were selected for mutation analysis, and the germline adenomatous polyposis coli (APC) gene mutation was detected. Eleven of 23 patients with FAP had duodenal polyps. During CE, jejunal-ileal polyps were detected in 7 of 23 FAPs, with a total number of 15 polyps in the ileum. The presence of duodenal adenomas was the only clinical feature predictive of small-bowel polyps. Identification of the ampulla of Vater was not achieved with CE; duodenal polyps were only seen in 4 of 11 patients identified endoscopically, with an underestimation of polyp numbers. APC mutations between codons 499 and 805 were associated with the absence of small-bowel polyps. CE is useful and safe for the surveillance of jejunal-ileal polyps in selected patients with FAP. CE is not useful in the surveillance of the duodenum where the majority of small-bowel cancers occur.