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Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases
  1. Isabel Spier1,2,
  2. Dmitriy Drichel3,
  3. Martin Kerick4,5,
  4. Jutta Kirfel2,6,
  5. Sukanya Horpaopan1,7,
  6. Andreas Laner8,9,
  7. Stefanie Holzapfel1,2,
  8. Sophia Peters1,
  9. Ronja Adam1,2,
  10. Bixiao Zhao10,
  11. Tim Becker3,11,
  12. Richard P Lifton10,
  13. Sven Perner12,
  14. Per Hoffmann1,13,14,
  15. Glen Kristiansen2,6,
  16. Bernd Timmermann15,
  17. Markus M Nöthen1,13,
  18. Elke Holinski-Feder8,9,
  19. Michal R Schweiger4,5,
  20. Stefan Aretz1,2
  1. 1Institute of Human Genetics, University of Bonn, Bonn, Germany
  2. 2Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany
  3. 3German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  4. 4Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  5. 5Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
  6. 6Institute of Pathology, University of Bonn, Bonn, Germany
  7. 7Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
  8. 8Medizinische Klinik—Campus Innenstadt, Klinikum der LMU, Munich, Germany
  9. 9MGZ—Center of Medical Genetics, Munich, Germany
  10. 10Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA
  11. 11Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
  12. 12Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany
  13. 13Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
  14. 14Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
  15. 15Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany
  1. Correspondence to Dr Isabel Spier, Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, Bonn D-53127, Germany; isabel.spier{at}


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.

  • Cancer: colon

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