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

Spier, I., Drichel, D., Kerick, M., Kirfel, J., Horpaopan, S., Laner, A., et al. (2015). Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases. Journal of Medical Genetics, 103468. doi:10.1136/jmedgenet-2015-103468.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-250A-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-250B-0
Genre: Journal Article

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Spier, Isabel , Author
Drichel, Dmitriy , Author
Kerick, Martin1, 2, Author
Kirfel, Jutta , Author
Horpaopan, Sukanya , Author
Laner, Andreas, Author
Holzapfel, Stefanie , Author
Peters, Sophia , Author
Adam, Ronja, Author
Zhao, Bixiao , Author
Becker, Tim, Author
Lifton, Richard P. , Author
Perner, Sven, Author
Hoffmann, Per, Author
Kristiansen, Glen , Author
Timmermann, Bernd3, Author              
Nöthen, Markus M. , Author
Holinski-Feder, Elke, Author
Schweiger, Michal R.1, 2, Author
Aretz, Stefan, Author
Affiliations:
1Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany , ou_persistent22              
2Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany , ou_persistent22              
3Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 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.

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Language(s): eng - English
 Dates: 2015-10-222015-11-27
 Publication Status: Published online
 Pages: -
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 Rev. Method: -
 Identifiers: DOI: 10.1136/jmedgenet-2015-103468
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Title: Journal of Medical Genetics
Source Genre: Journal
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Publ. Info: London : British Medical Association
Pages: - Volume / Issue: - Sequence Number: 103468 Start / End Page: - Identifier: ISSN: 0022-2593
CoNE: https://pure.mpg.de/cone/journals/resource/954925415940_2