title: Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis.
abstract: In up to 30% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. isabel.spier@uni-bonn.de.|Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany. isabel.spier@uni-bonn.de.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spier
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kerick
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Drichel
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Horpaopan
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.|Medizinisch Genetisches Zentrum, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Laner
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Holzapfel
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Peters
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Adam
authors.affiliation: Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Bixiao
authors.initials: B
authors.lastname: Zhao
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.affiliation: Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.|Medizinisch Genetisches Zentrum, Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.affiliation: Section for Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.|Pathology Network of the University Hospital of Luebeck and Leibniz Research Center Borstel, Borstel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D018256:Adenomatous Polyps / Q000235:genetics*; D000368:Aged; D051187:Desmocollins / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins; D007473:Ion Channels; C515204:PIEZO1 protein, human
keywords: Adenomatous polyposis; Candidate genes; Exome sequencing; Familial colorectal cancer; Hereditary tumor syndromes; Massive parallel sequencing