Familial Adenomatous Polyposis Gene Research Articles

Understanding the link between immunosuppressant and natural killer cell in the progression of autism: The role of natural killer cell and mammalian target of rapamycin in autistic brain

Natural killer cell plays a major role in the pathogenesis of neurodevelopmental disorder including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder that is associated with symptoms that reduce the quality of life of affected individuals such as social interaction deficit, cognitive impairment, intellectual disabilities, restricted, and repetitive behavioral patterns. This disorder begins in early childhood and continues throughout adulthood. ASD pathogenesis is associated with alteration in natural killer (NK) cells as well as mammalian target of rapamycin signaling functioning that leads to altered physiological processes during development. Here, we review literature highlighting the role of immunosuppressants especially rapamycin and azathioprine and their impact on treating the neurodevelopmental disorder and mechanism by which these drugs may act to ameliorate the autistic symptoms. Furthermore, this review discusses reports highlighting the role of NK cells and familial adenomatous polyposis gene in the etiology of ASD. This review suggests that further investigative work on these drugs could be vital in the management of ASD.

Study of diagnostic value of congenital hypertrophy of retinal pigment epithelium in Chinese familial adenomatous polyposis patients.

Congenital hypertrophy of retinal pigment epithelium (CHRPE) is an important characteristic of familial adenomatous polyposis (FAP) patients. However, more evidence about its sensitivity, specificity, and diagnostic value for FAP is needed to determine whether CHRPE is a reliable marker. Clinical features of FAP patients were investigated using in-person evaluations. Family members of FAP patients were evaluated with an indirect ophthalmoscope to determine whether they had CHRPE. We defined three diagnostic criteria for CHRPE (criteria A, B and C) based on their shape, quantity and size. Those with negative colonoscopy results and gene mutation results were classified as healthy controls. Of a total of 23 FAP families, 21 families were CHRPE-positive (91.3%). Among those 21 families, 47 individuals had CHRPE, including 33 FAP patients, 9 APC gene mutation carriers, and 5 individuals younger than 18 years who were later confirmed to have FAP. Fifty individuals had no CHRPE (5 FAP patients and 45 individuals without APC gene mutations and colorectal adenoma). The average number of CHRPE lesions per person was 5.81, and CHRPE was located mostly in the posterior pole in the eye fundus; 76.7% of individuals had CHRPE in both eyes. The sensitivity of the three CHRPE criteria ranged from 78.8 to 90.4%, with the highest sensitivity found for criterion A (90.4%), which had a specificity of 100% for healthy controls and sporadic colorectal cancer patients. CHRPE has vital diagnostic and screening value because of its high sensitivity for discovering FAP and APC gene mutation carriers.

Identification of Lynch syndrome risk variants in the Romanian population.

Two familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1,MSH2,MSH6,PMS2) and the genes APC and MUTYH, respectively. No information is available on the presence of high‐risk CRC mutations in the Romanian population. We performed whole‐genome sequencing of 61 Romanian CRC cases with a family history of cancer and/or early onset of disease, focusing the analysis on candidate variants in the LS and FAP genes. The frequencies of all candidate variants were assessed in a cohort of 688 CRC cases and 4567 controls. Immunohistochemical (IHC) staining for MLH1,MSH2,MSH6, and PMS2 was performed on tumour tissue. We identified 11 candidate variants in 11 cases; six variants in MLH1, one in MSH6, one in PMS2, and three in APC. Combining information on the predicted impact of the variants on the proteins, IHC results and previous reports, we found three novel pathogenic variants (MLH1:p.Lys84ThrfsTer4, MLH1:p.Ala586CysfsTer7, PMS2:p.Arg211ThrfsTer38), and two novel variants that are unlikely to be pathogenic. Also, we confirmed three previously published pathogenic LS variants and suggest to reclassify a previously reported variant of uncertain significance to pathogenic (MLH1:c.1559‐1G>C).

Cribriform-Morular Variant of Papillary Thyroid Carcinoma: Clinical and Pathological Features of 30 Cases.

Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is rare; it may occur in cases of familial adenomatous polyposis (FAP) or be sporadic. To clarify the clinicopathological features of CMV-PTC, the medical records of these patients were investigated retrospectively. Between 1979 and 2016, a total of 17,062 cases with PTC underwent initial surgery at Ito Hospital. Of these, 30 (0.2%) cases histologically diagnosed with CMV-PTC were reviewed. The patients were all women, with a mean age at the time of surgery of 24years. Seven (23%) cases were thought to have FAP because they had colonic polyposis or a family history of FAP or APC gene mutation. The remaining 23 (77%) were thought to be sporadic. Multiple tumors were detected in 6 cases, with a solitary tumor in 24. One patient had lung metastasis at diagnosis. Eleven patients underwent total thyroidectomy or subtotal thyroidectomy, and 19 underwent lobectomy. Twenty-six (87%) patients underwent neck lymph node dissection. Three patients had tumor metastasis in central lymph nodes, but these were incidentally detected metastatic classical PTC (cPTC) based on histological examination. In this series, there were no cases of LN metastases of CMV-PTC. During a mean follow-up of 15years, one patient had new cPTC in the remnant thyroid after initial surgery, and the other patients showed no signs of recurrence. CMV-PTC occurred in young women, their long-term prognosis was excellent. Total thyroidectomy is recommended for FAP-associated CMV-PTC, but modified neck lymph node dissection is not necessary.

Improving Mutation Screening in Patients with Colorectal Cancer Predisposition Using Next-Generation Sequencing

Identification of genetic alterations is important for family risk assessment in colorectal cancers. Next-generation sequencing (NGS) technologies provide useful tools for single-nucleotide and copy number variation (CNV) identification in many genes and samples simultaneously. Herein, we present the validation of current Multiplicom MASTR designs of mismatch repair combined to familial adenomatous polyposis genes in a single PCR reamplification test for eight DNA samples simultaneously on a MiSeq apparatus. Blood samples obtained from 224 patients were analyzed. We correctly identified the 97 mutations selected among 48 samples tested in a validation cohort. PMS2 NGS analysis of the eight positive controls identified single-nucleotide variations not detected with targeted referent methods. As NGS method could not discriminate if some of them were assigned to PMS2 or pseudogenes, only CNV analysis with multiplex ligand probe-dependent amplification confirmation was retained for clinical use. Twenty-seven new variants of unknown significance, 21 disease-causing variants, and two CNVs were detected among the 176 patient samples analyzed in diagnosis routine. MUTYH disease-causing mutations were identified in two patient samples assessed for mismatch repair testing, confirming that this method facilitates accurate and rapid individual risk assessments. In one sample, the MUTYH mutation was associated with a MSH6 disease-causing mutation, suggesting that this method is helpful to identify additional cancer risk modifiers and provides a useful tool to optimize clinical issues.

β-Catenin Mutations: Insights into the APC Pathway and the Power of Genetics.

See related article by Sparks et al., [Cancer Res 1998;58:1130–4][1] . Visit the Cancer Research 75th Anniversary [timeline][2]. In the mid 1990s, the human genome project was well underway, but it would still be more than 5 years before the first draft of the human genome was published and more

Analysis of Small Fragment Deletions of the APC gene in Chinese Patients with Familial Adenomatous Polyposis, a Precancerous Condition

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease mainly caused by mutations of the adenomatous polyposis coli (APC) gene with almost complete penetrance. These colorectal polyps are precancerous lesions that will inevitable develop into colorectal cancer at the median age of 40-year old if total proctocolectomy is not performed. So identification of APC germline mutations has great implications for genetic counseling and management of FAP patients. In this study, we screened APC germline mutations in Chinese FAP patients, in order to find novel mutations and the APC gene germline mutation characteristics of Chinese FAP patients. The FAP patients were diagnosed by clinical manifestations, family histories, endoscope and biopsy. Then patients peripheral blood samples were collected, afterwards, genomic DNA was extracted. The mutation analysis of the APC gene was conducted by direct polymerase chain reaction (PCR) sequencing for micromutations and multiplex ligation-dependent probe amplification (MLPA) for large duplications and/or deletions. We found 6 micromutations out of 14 FAP pedigrees, while there were no large duplications and/or deletions found. These germline mutations are c.5432C>T(p. Ser1811Leu), two c.3926_3930delAAAAG (p.Glu1309AspfsX4), c.3921_3924delAAAA (p.Ile1307MetfsX13), c3184_3187delCAAA(p.Gln1061AspfsX59) and c4127_4126delAT (p.Tyr1376LysfsX9), respectively, and all deletion mutations resulted in a premature stop codon. At the same time, we found c.3921_3924delAAAA and two c.3926_3930delAAAAG are located in AAAAG short tandem repeats, c3184_3187delCAAA is located in the CAAA interrupted direct repeats, and c4127_4128 del AT is located in the 5'-CCTGAACA-3' ,3'-ACAAGTCC-5 palindromes (inverted repeats) of the APC gene. Furthermore, deletion mutations are mostly located at condon 1309. Though there were no novel mutations found as the pathogenic gene of FAP in this study, we found nucleotide sequence containing short tandem repeats and palindromes (inverted repeats), especially the 5 bp base deletion at codon 1309, are mutations in high incidence area in APC gene.

Case report: intra-abdominal fibromatosis in familial adenomatous polyposis

Introduction Aggressive fibromatosis or intra-abdominal fibromatosis, also called ‘desmoid tumour’ is a benign rare tumour of fibrous origin that arises in deep soft tissues and is characterised by a high potential of local visceral invasion and recurrence. Five percent of desmoid tumours are associated with familial adenomatous polyposis (FAP) and 85% are sporadic. Case report An 18-year-old male with known FAP and adenomatous polyposis coli (APC) gene mutation presented with abdominal pain. Imaging showed a large soft tissue mass on the left side of mid small bowel mesentery. Histologically, the lesion was paucicellular with scattered bland spindle cells which showed strong nuclear positivity to B-catenin and stained negative for MSA, SMA and CD34, consistent with desmoid tumour. Discussion The pathogenesis of desmoid tumour is multifactorial and includes genetics, trauma, and endocrine factors. About 85% of desmoid tumours occur sporadically and only 5% occur in conjunction with Gardner-type familial adenomatous polyposis (FAP) with associated APC gene mutation. Mutations in the B-catenin encoding CTNNB1 gene have been proposed in the sporadic cases. Majority of desmoid tumours are amenable to surgical resection but if complete resection is unfeasible due to significant morbidity, radiotherapy and/or chemotherapy are the other treatment modalities of choice.

Novel insertion mutation p.Asp610GlyfsX23 in APC gene causes familial adenomatous polyposis in Chinese families

ObjectiveThe aim of the study was to identify the causative gene defects associated with familial adenomatous polyposis (FAP) in two Chinese pedigrees. MethodsThe diagnosis of FAP patients was confirmed by clinical manifestations, family histories, colonoscopy and pathology examinations. Blood samples were collected and genomic DNA was extracted. The mutation analysis of the adenomatous polyposis coli (APC) and human mutY homolog (MUTYH) genes was conducted by direct polymerase chain reaction (PCR) sequencing and multiplex ligation-dependent probe amplification (MLPA). ResultsIn pedigree A, the results of direct PCR sequencing revealed a heterozygous insertion mutation at codon 610 in exon 15 of APC gene (c.1828_1829insG), which resulted in frameshift change (p.Asp610GlyfsX23) in all 4 patients, but was absent in the unaffected familial members and controls. In pedigree B, we didn't identify that causative mutations cosegregated with the clinical phenotype in the APC and MUTYH genes. ConclusionsWe identified a novel insertion mutation as the pathogenic gene of FAP in Chinese population, which could enrich the germline mutation spectrum of APC gene, and the prophylactic proctocolectomy for the mutation carrier in family should be considered.

CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics

Desmoid tumors are benign monoclonal fibroblastic or myofibroblastic neoplasms, characterized by local invasiveness and high rates of recurrence. Desmoid tumors must be distinguished from benign fibroblastic and myofibroblastic lesions, as well as from low-grade sarcoma, which can appear histologically similar to desmoid tumors. This differential diagnosis can be very difficult, especially when diagnosis is based on a core needle biopsy. On the molecular level, most sporadic desmoid tumors are associated with mutations of the β-catenin gene (CTNNB1). A minority of desmoid tumors are associated with Gardner syndrome and mutations of the familial adenomatous polyposis gene. We identified the common CTNNB1 mutations associated with sporadic desmoid tumors by direct sequencing: in (i) 260 cases of typical desmoid tumors; and (ii) in 191 cases of spindle cell lesions, which can morphologically ‘mimic’ desmoid tumors. Formalin-fixed paraffin-embedded tissues were obtained via core needle biopsy (n=150) or open biopsy/surgical excision (n=301). Only 16 cases (4%) were not analyzable (Bouin's fixed tissue). CTNNB1 mutations were observed in 223 of 254 (88%) of sporadic desmoid tumors. No CTNNB1 mutations were detected in all other lesions (n=175) studied. CTNNB1 sequencing can be easily and reliably done using tissues obtained via core needle biopsy. Detection of CTNNB1 mutations in formalin-fixed paraffin-embedded tissues among spindle cell lesions is proposed as a specific diagnostic tool for the diagnosis of desmoid tumors. This result has significant implications for patient care and management.

Lessons from the hepatoblastoma-familial polyposis connection

Approximately one-third of hepatoblastoma (HB) patients have associated congenital abnormalities, but familial recurrence is rare, except in association with familial adenomatous polyposis (FAP). This correlation may be missed if not actively sought, with implications for long-term outcome and management. We retrospectively investigated 3 families with an HB-familial polyposis connection, from a cohort of 113 FAP families (1989 - 2010). Data were analysed to assess clinical problem, treatment, complications and management. Long-term morbidity and functional outcome were analysed to identify management difficulties. Three FAP families (2.65%) had an HB association. In one case, undiagnosed FAP at the time of HB diagnosis was only detected 5 years later, when the mother presented with advanced colorectal carcinoma. A chromosome 5 APC gene mutation (exon 15 codon 793 C→T) was then identified. In a second case, a non-related male child presented with a stage 4 multifocal HB with lung metastases. Genetic studies identified an APC gene mutation (exon 6 codon 232 C→T). Further family investigation showed >20 related FAP patients. A third HB-FAP association was identified in a known FAP family early in the study, prior to the availability of genetic testing. Although a rare association, a family history of FAP in HB patients is an important 'hidden connection'. Germline variation may be outside the usual FAP gene site. Identifying families with unknown HB/FAP is important due to long-term management implications and follow-up.

P-0234 Surgical Approach to the Familial Adenomatous Polyposis According to the Genetic Basis

ABSTRACT Introduction Familial adenomatous polyposis (FAP) is an autosomic dominant syndrome defined by the presence of more than a hundred colonic adenomatous polyps. It results from germline mutations in APC gene. In FAP, the risk of malignant transformation is 100%, thus the need for prophylactic surgery is beyond question. Debate exists about which surgical technique should be carried out. Although, proctocolectomy with ileal pouch-anal anastomosis has been practiced more often, because of its postoperative complications and the impact on quality of life, other less extensive resections have been accomplished in some particular cases. Nowadays, there is a preference for individualized treatment, based upon genotype-phenotype correlations. Methods We present two cases showing different surgical treatment based on the location of the mutation within APC gene. Results CASE 1: A 28-year-old female with a family history of FAP was evaluated at the High Risk CRC Unit of our institution. A diagnostic colonoscopy was carried out in which more than 100 polyps were found along the whole length of the large bowel, including more than 20 in the rectum. Biopsies from some of them were reported as adenomatous polyps without dysplasia in any of them. A genetic analysis was carried out on her. A mutation in the APC gene was detected (exon 7, c.268 G>T). Due to these clinical and molecular findings, she underwent prophylactic surgery, in which a proctocolectomy with ileal pouch-anal anastomosis was carried out. CASE 2: A 45- year-old male, with a medical history of only hypertension, osteochondrosis and gastroesophageal reflux disease, without any familial predisposition to cancer. He was examined in our institution because of nonspecific abdominal symptoms. A colonoscopy was carried out, which showed many polyps along the large bowel. In the rectum, only one lesion was found with same characteristics. Biopsies from some of them were reported as adenomatous polyps with several dysplasias. A mutation in the APC gene was detected (exon 1. c70c>T). The patient underwent total colectomy with ileorectal anastomosis, exceeding the rectal polyp. Conclusion Nowadays, it is recognised that a correlation might exist between the site of mutations in APC gene and clinical phenotype of FAP. Whilst, some mutations have been associated with the severity of colonic polyposis (case 1), others lead to attenuated forms of the disease (case 2). In the same way, the extracolonic manifestations of FAP, as upper intestinal tumors and desmoids, have also been correlated with the site of APC mutation. Therefore, the debate continuous about which operation should be carried out. Up to now, proctocolectomy was considered when >1000 polyps develop, a large number in the rectum, when rectal adenomas >3 cm are found, or when advanced histology appears. However, we support the idea that these recommendations should be completed with the consideration of the site of the mutations in the gene APC. This work was funded by the Spanish Fondo de Investigaciones Sanitarias (grant number FIS-PI10/0683).

Clinical report. Benefits from genetic test in descendants of familial adenomatous polyposis syndrome: report of a family in southern Thailand

Abstract Background: Familial adenomatous polyposis (FAP) is an inherited colorectal cancer predisposing syndrome that has an autosomal dominant mode of inheritance with complete penetrance. Although the disease-causing gene of FAP, the adenomatous polyposis coli (APC) gene, is well understood, genetic testing for FAP remains uncommon in Thailand, possibly because of its high cost. Objective: Present a family in southern Thailand that had benefited from this test. Subject and methods: The proband was a 31-year-old man who had rectal cancer with profuse adenomatous polyposis of his colon. Results: APC mutation screening revealed a novel mutation at codon 1249 (TGC1249TAA) that could predict a premature stop codon. On screening of three siblings in the same generation who were alive and 11 members of the descendant generation, four cases were positive for the mutation. The positive members were confirmed to have a type of diffuse colonic polyposis by endoscopy, and a prophylactic colectomy was performed without complications for every affected individual. Conclusion: A genetic test is cost-effective. It should be considered for FAP, especially when the number of at-risk family members is high.

Benefits from genetic test in descendants of familial adenomatous polyposis syndrome: report of a family in southern Thailand

Background: Familial adenomatous polyposis (FAP) is an inherited colorectal cancer predisposing syndrome that has an autosomal dominant mode of inheritance with complete penetrance. Although the disease-causing gene of FAP, the adenomatous polyposis coli (APC) gene, is well understood, genetic testing for FAP remains uncommon in Thailand, possibly because of its high cost. Objective: Present a family in southern Thailand that had benefited from this test. Subject and methods: The proband was a 31-year-old man who had rectal cancer with profuse adenomatous polyposis of his colon. Results: APC mutation screening revealed a novel mutation at codon 1249 (TGC1249TAA) that could predict a premature stop codon. On screening of three siblings in the same generation who were alive and 11 members of the descendant generation, four cases were positive for the mutation. The positive members were confirmed to have a type of diffuse colonic polyposis by endoscopy, and a prophylactic colectomy was performed without complications for every affected individual. Conclusion: A genetic test is cost-effective. It should be considered for FAP, especially when the number of at-risk family members is high. Keywords: Adenomatous polyposis syndrome, APC gene, familial adenomatous polyposis coli

Cáncer hereditario de colon: Aportes del diagnóstico genético molecular

About 30% of cases of colon cancer (CC) have a family history of CC, and only 5% are hereditary forms. Hereditary forms have an increased risk of CC and other tumors.To report the molecular and genetic study in two families with hereditary CC.Molecular analysis of the adenomatous polyposis coli (APC) gene of familial adenomatous polyposis (FAP), was done in a patient with multiple benign polyps and his children. Molecular analysis was performed for MLH1 gene mutation of hereditary non-polyposis colon cancer (HNPCC) in an asymptomatic patient with family history of multiple cancers and his mother with a confirmed mutation in the MLH1 gene.The patient with FAP had an insertion of 17 base pairs in exon 9 of the APC gene and two of his children had the same mutation. The patient with history of HNPCC did not have the family mutation on MLH1.In the case of FAP, molecular study was performed in his children since manifestations in carriers of the mutation may begin in childhood. If the second patient would have had the mutation, the study of his children could have been postponed until the age of 18, when the risk for CC is increased.

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

Mutated in colorectal cancer (MCC) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAF(V600E) mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with beta-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, beta-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, beta-catenin-interacting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/beta-catenin signal transduction.

DHPLC Analysis of Adenomatous Polyposis Coli (APC) Mutations Using Ready-to-Use APC Plates: Simple Detection of Multiple Base Pair Deletion Mutations

The adenomatous polyposis coli (APC), which is the susceptible gene for familial adenomatous polyposis (FAP) and sporadic colorectal cancer, spans 15 exons. The open reading frame of APC is 8529 bp, which encodes 2843 amino acids. Conventional genetic screening involves extensive time as well as high cost and labor. Thus, we developed a novel APC ready-to-use plate for high-throughput mutational analysis by denaturing high performance liquid chromatography (DHPLC). To prepare the ready-to-use APC plate, all 38 primer pairs and PCR mixtures were aliquoted into individual wells of a 96-well plate, and frozen at -20 degrees C until use. All 38 PCR primers were designed to be amplified at the same temperature (52 degrees C). We examined a total of 27 FAP patient samples with APC germline mutations (17 for multiple bp deletions, 1 for 1 bp deletion, 9 for nonsense mutations) and 50 APC-negative noncarriers. All 17 multiple bp deletion mutations were detected during the initial 50 degrees C running analysis and thus ruled out for further analyses. All other mutations were clearly detected under specific optimized conditions. More than 50% of the APC germline mutations were multiple base pair deletions and efficiently selected by omitting time-consuming partial denaturing conditions.

The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse

The morphological changes associated with the adenoma-carcinoma sequence are well documented in the colorectum. Small intestinal carcinogenesis is thought to progress through a similar adenoma-to-carcinoma pathway, but there is a relative dearth of studies examining the associated morphological changes. The best-known mouse model of intestinal neoplasia, the multiple intestinal neoplasia (Min) mouse, has been criticized as a genetic model of intestinal neoplasia, as the majority of its tumours occur in the small intestine. We examined pancreatico-duodenal resection specimens from seven familial adenomatous polyposis (FAP) patients. Serial sections of these were stained with haematoxylin and eosin for beta-catenin and its downstream target CD44, for BMPR1a, lysozyme, carbonic anhydrase II, and with MIB-1. Individual dysplastic crypts were isolated and mutations in the FAP (APC) gene compared between the top and bottom of the crypt. We found that: (a) duodenal microadenomas are extremely common in FAP patients; (b) these grow in the core of duodenal villi, forming lesions similar to those described in the Min mouse; (c) many lesions arise as monocryptal adenomas and grow by a process of crypt fission and branching; (d) migrating adenomatous cells lose their dysplastic phenotype as they migrate up the crypt villous axis; and (e) Paneth cells lose positional information. (a) the morphological similarity of adenomas in the Min mouse and human suggest the Min mouse is a good model of FAP; (b) duodenal adenomas in FAP originate in monocryptal adenomas and follow the 'bottom-up' rather than the 'top-down' model of morphogenesis; (c) early microadenomas show evidence of cellular differentiation; (d) defects in the positioning of Paneth cells suggests disruption of the EphB2:EphB3 receptor system.

Brain tumors in individuals with familial adenomatous polyposis

Most individuals with Familial Adenomatous Polyposis (FAP) harbor mutations in the APC gene on chromosome 5q21. They are at an increased risk of brain tumors, including cerebellar medulloblastoma, when compared with the general population (Brain Tumor Polyposis-BTP Type 2). Genotype-phenotype correlations between APC gene mutations and central nervous system (CNS) tumors have, thus far not been successful. Herein the authors have pooled their registry experience in BTP type 2 with the published reports. The authors analyzed their established hereditary CRC Registry for brain tumors in FAP pedigrees (56 families, 213 individuals), pooled their patients with BTP and known APC mutations with those reported thus far elsewhere, and compared the resulting mutation distribution of FAP-BTP with the mutation distribution for APC mutations in the US. Twenty-eight patients from 24 families were accrued, the most common brain tumor in BTP was medulloblastoma (60%) predominantly in females (12:5) under the age of 20 (mean age 14.7 SD 9.2). Other histologic subtypes included astrocytoma and ependymoma. Analysis of the pooled APC mutation data by Chi-square test of association shows an odds ratio of 3.7 (P < .005) for all brain tumor subtypes and 13.1 (P < .001) for medulloblastoma in patients harboring segment 2 APC mutation (codons 679-1224) compared to nonsegment 2 mutation. In patients with FAP and identifiable APC gene mutation, CNS tumors, especially medulloblastoma which developed in most cases during childhood, are more common in females with FAP and APC gene mutation in codons 686-1217. Further studies are necessary to determine if this observation and the natural history of medulloblastoma in children justifies novel, aggressive, targeted screening of at-risk individuals.

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant condition resulting in the development of more than 100 adenomatous polyps in the large bowel. In addition, a number of extracolonic manifestations of the condition may occur. Recently, increasing knowledge relating to the extracolonic abnormalities, and localization and sequencing of the gene for FAP, have had important implications for screening and long-term follow-up of those affected. In this review the natural history of the disease and the extracolonic manifestations associated with it are considered. Surgical management and advances in understanding at a molecular level are discussed, as well as the problems relating to screening for FAP and the implications of the new knowledge.