Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases

Isabel Spier¹, Dmitriy Drichel², Martin Kerick³, Jutta Kirfel⁴, Sukanya Horpaopan⁵, Andreas Laner⁶, Stefanie Holzapfel¹, Sophia Peters⁷, Ronja Adam¹, Bixiao Zhao⁸, Tim Becker⁹, Richard P Lifton⁸, Sven Perner¹⁰, Per Hoffmann¹¹, Glen Kristiansen⁴, Bernd Timmermann¹², Markus M Nöthen¹³, Elke Holinski-Feder⁶, Michal R Schweiger³, Stefan Aretz¹

Affiliations

¹ Institute of Human Genetics, University of Bonn, Bonn, Germany Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
² German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
³ Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
⁴ Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany.
⁵ Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
⁶ Medizinische Klinik-Campus Innenstadt, Klinikum der LMU, Munich, Germany MGZ-Center of Medical Genetics, Munich, Germany.
⁷ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸ Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
⁹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
¹⁰ Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
¹¹ 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.
¹² Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
¹³ Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

PMID: 26613750
DOI: 10.1136/jmedgenet-2015-103468

Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases

Isabel Spier et al. J Med Genet. 2016 Mar.

. 2016 Mar;53(3):172-9.

doi: 10.1136/jmedgenet-2015-103468. Epub 2015 Nov 27.

Authors

Affiliations

¹ Institute of Human Genetics, University of Bonn, Bonn, Germany Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.
² German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
³ Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
⁴ Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany Institute of Pathology, University of Bonn, Bonn, Germany.
⁵ Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
⁶ Medizinische Klinik-Campus Innenstadt, Klinikum der LMU, Munich, Germany MGZ-Center of Medical Genetics, Munich, Germany.
⁷ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸ Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
⁹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
¹⁰ Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
¹¹ 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.
¹² Next Generation Sequencing Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
¹³ Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

PMID: 26613750
DOI: 10.1136/jmedgenet-2015-103468

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.

Keywords: Cancer: colon.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases

Affiliations

Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases

Authors

Affiliations

Abstract

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials