title: Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.
abstract: BACKGROUND
  In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis.
  
  
  METHODS
  To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ≥ 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods.
  
  
  RESULTS
  In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene.
  
  
  CONCLUSIONS
  The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spier
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Drichel
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: Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Horpaopan
authors.affiliation: Medizinische Klinik-Campus Innenstadt, Klinikum der LMU, Munich, Germany MGZ-Center of Medical Genetics, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Laner
authors.affiliation: Institute of Human Genetics, University of Bonn, 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, Bonn, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Peters
authors.affiliation: Institute of Human Genetics, University of Bonn, 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, Connecticut, 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, Connecticut, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
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: Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Medizinische Klinik-Campus Innenstadt, Klinikum der LMU, Munich, Germany MGZ-Center of Medical Genetics, Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
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, 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*; D000293:Adolescent; D000328:Adult; D015179:Colorectal Neoplasms / Q000235:genetics; D017491:Genes, APC; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate
keywords: Cancer: colon