Universität zu Köln

Spier, Isabel, Drichel, Dmitriy ORCID: 0000-0001-5978-3458, Kerick, Martin ORCID: 0000-0002-6298-4514, Kirfel, Jutta, Horpaopan, Sukanya, Laner, Andreas, Holzapfel, Stefanie, Peters, Sophia, Adam, Ronja, Zhao, Bixiao ORCID: 0000-0002-1775-1690, Becker, Tim, Lifton, Richard P., Perner, Sven, Hoffmann, Per, Kristiansen, Glen, Timmermann, Bernd, Noethen, Markus M., Holinski-Feder, Elke, Schweiger, Michal R. and Aretz, Stefan ORCID: 0000-0002-5228-1890 (2016). Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases. J. Med. Genet., 53 (3). S. 172 - 180. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Spier, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Drichel, Dmitriy UNSPECIFIED orcid.org/0000-0001-5978-3458 UNSPECIFIED Kerick, Martin UNSPECIFIED orcid.org/0000-0002-6298-4514 UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Horpaopan, Sukanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Laner, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzapfel, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Peters, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Adam, Ronja UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Bixiao UNSPECIFIED orcid.org/0000-0002-1775-1690 UNSPECIFIED Becker, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Lifton, Richard P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Perner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Per UNSPECIFIED UNSPECIFIED UNSPECIFIED Kristiansen, Glen UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmermann, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Noethen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holinski-Feder, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-283234
DOI:	10.1136/jmedgenet-2015-103468
Journal or Publication Title:	J. Med. Genet.
Volume:	53
Number:	3
Page Range:	S. 172 - 180
Date:	2016
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1468-6244
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SOMATIC MOSAICISM; GERMLINE MUTATIONS; MUTYH; GENES; RISK; PREDISPOSE; PREVALENCE; DELETIONS; VARIANTS; SPECTRUM Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28323