title: Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists.
abstract: Two main colorectal polyposis syndromes have been described, familial adenomatous polyposis and MUTYH-associated polyposis syndromes. Some polyposis remains unexplained: 20% of adenomatous polyposis and serrated polyposis. The aim of this study was to evaluate in a cohort of patients with unexplained polyposis whether a genetic defect could be detected. Individuals presenting polyposis with more than 40 adenomas or more than 20 serrated polyps (hyperplastic, sessile serrated and mixed), without causative mutation identified, were included. Complementary explorations on APC or MUTYH were performed: search for APC mosaicism, splicing-affecting mutations, large genomic rearrangement of MUTYH. Four genes of Wnt pathway (AXIN2, PPP2R1B, WIF1, SFRP1) and two genes of transforming growth factor-β (TGF-β) pathway (SMAD4, BMPR1A) were screened for germline mutation. Twenty-five patients had an unexplained adenomatous polyposis (familial or sporadic). Five pathogenic mutations were found: four in APC gene (with one case of mosaicism) and one in BMPR1A gene. The exploration of APC mosaicism was better performed from adenoma DNA with high-resolution melting. The screening of the candidate genes did not find any causative mutation. Thirteen individuals had an unexplained serrated polyposis and a frameshift on SMAD4 gene was identified. All mutations were identified in familial cases of polyposis. After new pathological examination, both BMPR1A and SMAD4 cases were found to be associated with a juvenile polyposis while the polyposis was initially described as adenomatous or undetermined. In 17% (6/38) of the patients the causative mutation of the polyposis was identified. Genetic causes were heterogeneous. Sporadic polyposis patients must be considered as potential APC mosaicism. The histological classification of polyposis is strongly important in direct genetic exploration.
authors.affiliation: Oncogenetic and Molecular Angiogenetic Laboratory, Hospital Pitié-Salpêtrière AP-HP, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Mongin
authors.forename: F
authors.initials: F
authors.lastname: Coulet
authors.forename: J H
authors.initials: JH
authors.lastname: Lefevre
authors.forename: C
authors.initials: C
authors.lastname: Colas
authors.forename: M
authors.initials: M
authors.lastname: Svrcek
authors.forename: M
authors.initials: M
authors.lastname: Eyries
authors.forename: Y
authors.initials: Y
authors.lastname: Lahely
authors.forename: J-F
authors.initials: JF
authors.lastname: Fléjou
authors.forename: F
authors.initials: F
authors.lastname: Soubrier
authors.forename: Y
authors.initials: Y
authors.lastname: Parc
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D015331:Cohort Studies; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D005767:Gastrointestinal Diseases / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009030:Mosaicism; D009691:Nucleic Acid Denaturation; D017354:Point Mutation; D051901:Smad4 Protein / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D052005:Bone Morphogenetic Protein Receptors, Type I; D045647:DNA Glycosylases; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051901:Smad4 Protein; C555337:APC protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C497796:SMAD4 protein, human; C498211:BMPR1A protein, human; C061738:mutY adenine glycosylase