4089

SMAD4

DPC4|JIP|MADH4;SMAD family member 4;SMAD4;SMAD family member 4

MAD homolog 4|SMAD, mothers against DPP homolog 4|deleted in pancreatic carcinoma locus 4|deletion target in pancreatic carcinoma 4|mothers against decapentaplegic homolog 4|mothers against decapentaplegic, Drosophila, homolog of, 4

18q21.1

protein-coding

Juvenile polyposis is an uncommon condition characterized by the development of multiple (usually more than 5) juvenile polyps in the gastrointestinal tract, especially in the colon. This disease usually occurs during childhood, and is inherited in an autosomal dominant fashion. It has been suggested that the dpc4 (deleted in pancreatic carcinoma, locus 4) gene, which is located on chromosome 18q21.1, might cause juvenile polyposis. The dpc4 (smad4) gene is a candidate tumor-suppressor gene and may play a role in the TGF-beta-signaling pathway. To confirm the idea that alterations of the dpc4 gene may result in juvenile polyposis, we screened 5 Korean juvenile-polyposis patients by PCR-SSCP (single-strand conformation polymorphism) analysis and bi-directional sequencing. There were germline mutations of the dpc4 gene in 3 out of the 5 patients: 2 hada genetic alteration in exon 9 and the third had a mutation in exon 8. These germline mutations occurred in the C-terminus of the dpc4 gene, similar to most published mutations. One patient exhibited a non-sense mutation (codon 388), which changed a glutamine codon (CAG) to a stop codon (TAG). The second patient harbored a mis-sense mutation (codon 390), causing a non-conservative amino-acidchange . The third patient had a mis-sense mutation in exon 8 (codon 361), which altered an arginine codon (CGC) into a histidine codon (CAC).#CI- Copyright 2000 Wiley-Liss, Inc.

Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductaladenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/beta-catenin pathway and chromosome 11p, using immunohistochemistry for beta-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterationsfound in adult-type pancreatic ductal adenocarcinomas including mutations in theK-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelicloss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86% (six of seven informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the beta-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasmsshowed abnormal nuclear accumulation of beta-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the morecommon pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracolonicmanifestation of FAP.

BTI - GeneReviews#. Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk ofGI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4 mutation. JPS is clinically diagnosed if any one of the three following findings is present: More than five juvenile polyps of the colorectum . Multiple juvenile polyps throughout the GI tract . Any number of juvenile polyps and a family history of juvenile polyps . Juvenile polyps are hamartomas with a distinct histology that differs from that of adenomas. The genes known to be associated with JPS are BMPR1A and SMAD4. Approximately 20% ofindividuals with JPS have mutations in BMPR1A; approximately 20% have mutations in SMAD4. Molecular genetic testing of both genes is available on a clinical basis. Treatment of manifestations: Routine colonoscopy with endoscopic polypectomy to reduce the risk of bleeding, intestinal obstruction, and colon cancer. When the number of polyps is large, removal of ALL or part of the colon or stomach may be necessary. Treatment as needed for manifestations of HHT. Prevention of primary manifestations: cancer prevention/risk reduction through cancer screening. Surveillance: For individuals at risk: monitoring for rectal bleeding and/or anemia, abdominal pain, constipation, and diarrhea; screening bycomplete blood count (CBC), colonoscopy, and upper endoscopy starting in the mid-teens (age 15 years) or earlier when symptoms occur. In families with the combined JPS/HHT syndrome and/or a known SMAD4 mutation, predictive molecular genetic testing may be appropriate before age 15 years as surveillance for potential complications of HHT begins in early childhood. Evaluation of relatives at risk: When the family-specific mutation is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention. JPS is inherited in an autosomal dominant manner. Approximately 75% of individuals with JPS have an affected parent; approximately 25% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of a new gene mutation. Each child of an affected individual has a 50% chance of inheriting the mutation and developing JPS. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. Requests for prenatal testing for conditions which (like JPS) are treatable and do not affect intellect are not common.#CI- Copyright (c) 1993-2013, University of Washington, Seattle. ALL rights reserved.#FED - Pagon, Roberta A#ED- Pagon RA#FED - Adam, Margaret P#ED- Adam MP#FED - Bird, Thomas D#ED- Bird TD#FED - Dolan, Cynthia R#ED- Dolan CR#FED - Fong, Chin-To#ED- Fong CT#FED - Stephens, Karen#ED- Stephens K#FAU - Larsen Haidle, Joy

SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the membersof this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile polyposis hereditary hemorrhagic telangiectasia syndrome (JP/HHT; OMIM#17505). Hematochezia and colonic mucosal inflammation suggestive of inflammatory bowel diseases (IBD) have been reported in JP/HHT. Stimulated by recent experience with two affected pediatric patients presented here, we explored the potential role of Smad4 haploinsufficiency in a murine model of colonic inflammation. Smad4(+/-) mice were maintained on a mixed C57/129SvEv background. Chronic colitis was induced with repeated administration of dextran sulfate sodium (DSS) in drinkingwater. The colonic mucosal microbiota was interrogated by massively parallel pyrosequencing of the bacterial 16S rRNA gene. 66.7% of Smad4(+/-) mice were sensitive to DSS colitis compared to 14.3% of wild type (Chi-Square p=0.036). The augmented colitis was associated with microbiota separation in the Smad4(+/-) mice. Enterococcus and Enterococcus faecalis specifically was increased in abundance in the colitis-prone animals. Smad4 haploinsufficiency can associate with increased susceptibility to large bowel inflammation in mammals with variable penetrance in association with the colonic mucosal microbiota. These findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well.