Universität zu Köln

Spier, Isabel, Kerick, Martin ORCID: 0000-0002-6298-4514, Drichel, Dmitriy ORCID: 0000-0001-5978-3458, Horpaopan, Sukanya, Altmueller, Janine, Laner, Andreas, Holzapfel, Stefanie, Peters, Sophia, Adam, Ronja, Zhao, Bixiao ORCID: 0000-0002-1775-1690, Becker, Tim, Lifton, Richard P., Holinski-Feder, Elke, Perner, Sven, Thiele, Holger, Noethen, Markus M., Hoffmann, Per, Timmermann, Bernd, Schweiger, Michal R. and Aretz, Stefan ORCID: 0000-0002-5228-1890 (2016). Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis. Fam. Cancer, 15 (2). S. 281 - 289. DORDRECHT: SPRINGER. ISSN 1573-7292

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Spier, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kerick, Martin UNSPECIFIED orcid.org/0000-0002-6298-4514 UNSPECIFIED Drichel, Dmitriy UNSPECIFIED orcid.org/0000-0001-5978-3458 UNSPECIFIED Horpaopan, Sukanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine 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 Holinski-Feder, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Perner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Noethen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Per UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmermann, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-279122
DOI:	10.1007/s10689-016-9870-z
Journal or Publication Title:	Fam. Cancer
Volume:	15
Number:	2
Page Range:	S. 281 - 289
Date:	2016
Publisher:	SPRINGER
Place of Publication:	DORDRECHT
ISSN:	1573-7292
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GERMLINE MUTATIONS; CANCER; CARCINOMAS; VARIANTS; DISEASE; CELLS; CDX2; POLE Multiple languages Oncology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27912