title: Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers.
abstract: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about 40-50% of patients. Little is known, however, about the occurrence and nature of somatic alterations (2nd-hit) in SMAD4-/BMPR1A-related juvenile polyps. In this study, we screened 25 polyps from three patients carrying either a pathogenic SMAD4 (c.1244-1247delACAG) or BMPR1A (c.583C>T; p.Gln195*) germline mutation for somatic alterations. The SMAD4-related polyps were also analyzed for SMAD4 protein expression by immunohistochemistry. Despite comprehensive screening for loss of heterozygosity (LOH), mutations in the coding sequence, chromosomal rearrangements, and promoter methylation, no somatic alterations could be identified in 14 SMAD4-related polyps. SMAD4 protein expression, however, was lost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, the epithelial and stromal, compartments. In the BMPR1A-related polyps, five out of nine (56%) displayed LOH. Further analysis of selected polyps revealed that LOH was gene copy number neutral and had occurred in the epithelial compartment. The heterogeneity of genetic mutations and protein expression levels indicates that different modes of gene inactivation can be operational in SMAD4- and BMPR1A-related polyp formation. Our observation, that about half of BMPR1A-related polyps displayed LOH, predominantly in the epithelial compartment, is compatible with BMPR1A acting as a tumour suppressor gene. Still, it remains to be determined whether juvenile polyp development generally requires loss of BMPR1A expression or, as observed in some SMAD4-related polyps, can occur despite normal protein expression.
authors.affiliation: Research Group Human Genomics, Department of Biomedicine, University of Basel, Basel, 4031, Switzerland.
authors.forename: Robert H E
authors.initials: RH
authors.lastname: Blatter
authors.affiliation: Research Group Human Genomics, Department of Biomedicine, University of Basel, Basel, 4031, Switzerland.|Institut Für Klinische Genetik, Klinikum Stuttgart-Olgahospital, Stuttgart, 70174, Deutschland.
authors.forename: Martina
authors.initials: M
authors.lastname: Plasilova
authors.affiliation: Medical Genetics, University Hospital Basel, Basel, 4055, Switzerland.
authors.forename: Friedel
authors.initials: F
authors.lastname: Wenzel
authors.affiliation: Department of Pathology, UT Southwestern Medical School, Dallas, TX.
authors.forename: Sefik T
authors.initials: ST
authors.lastname: Gokaslan
authors.affiliation: Department of Pathology, University Hospital Basel, Basel, 4003, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Miraca Life Sciences, Irving, TX, 75039.
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.affiliation: Research Group Human Genomics, Department of Biomedicine, University of Basel, Basel, 4031, Switzerland.|Medical Genetics, University Hospital Basel, Basel, 4055, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
mesh_terms: D000328:Adult; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D006801:Humans; D044483:Intestinal Polyposis / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D019656:Loss of Heterozygosity; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I