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Fam Cancer. 2016 Apr;15(2):281-8. doi: 10.1007/s10689-016-9870-z.

Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis.

Author information

  • 1Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
  • 2Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
  • 3Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 4Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 5German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • 6Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
  • 7Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
  • 8Institute of Human Genetics, University of Cologne, Cologne, Germany.
  • 9Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
  • 10Medizinisch Genetisches Zentrum, Munich, Germany.
  • 11Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
  • 12Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
  • 13Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
  • 14Section for Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
  • 15Pathology Network of the University Hospital of Luebeck and Leibniz Research Center Borstel, Borstel, Germany.
  • 16Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
  • 17Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.
  • 18Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 19Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.


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.


Adenomatous polyposis; Candidate genes; Exome sequencing; Familial colorectal cancer; Hereditary tumor syndromes; Massive parallel sequencing

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