title: Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas.
abstract: Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9(V90M) had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Division of Medical Oncology, National Cancer Centre, Singapore; Oncology Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Wanfeng
authors.initials: W
authors.lastname: Yu
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lamis
authors.initials: L
authors.lastname: Yehia
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Farshad
authors.initials: F
authors.lastname: Niazi
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jinlian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Molecular and Cell Biology, A∗STAR, Singapore.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Tang
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Brandie
authors.initials: B
authors.lastname: Heald
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Junying
authors.initials: J
authors.lastname: Lei
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Todd
authors.initials: T
authors.lastname: Romigh
authors.affiliation: Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Lisa
authors.initials: L
authors.lastname: Tucker-Kellogg
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Kiat Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, A∗STAR, Singapore.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Song
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio. Electronic address: engc@ccf.org.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D003111:Colonic Polyps / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004067:Digestive System Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D015536:Down-Regulation; D059472:Exome; D005260:Female; D005729:Ganglioneuroma / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018814:Multiple Endocrine Neoplasia Type 2b / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010580:Peutz-Jeghers Syndrome / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D051904:Smad8 Protein / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C107514:SMAD9 protein, human; D051904:Smad8 Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Colorectal Cancer; Ganglioneuromas; Hamartomatous Polyps; SMAD Signaling