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  Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis

Spier, I., Kerick, M., Drichel, D., Horpaopan, S., Altmüller, J., Laner, A., et al. (2016). Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis. Famillial Cancer, 2016, 1-8. doi:10.1007/s10689-016-9870-z.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-6B80-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-6B81-5
Genre: Journal Article

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 Creators:
Spier, Isabel , Author
Kerick, Martin1, Author              
Drichel, Dmitriy, Author
Horpaopan, Sukanya , Author
Altmüller, Janine, Author
Laner, Andreas, Author
Holzapfel, Stefanie , Author
Peters, Sophia , Author
Adam, Ronja, Author
Zhao, Bixiao, Author
Becker, Tim, Author
Lifton, Richard P. , Author
Holinski-Feder, Elke, Author
Perner, Sven, Author
Thiele, Holger, Author
Nöthen, Markus M. , Author
Hoffmann, Per, Author
Timmermann, Bernd1, Author              
Schweiger, Michal R. , Author
Aretz, Stefan, Author
Affiliations:
1Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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Free keywords: Familial colorectal cancer; Adenomatous polyposis; Candidate genes; Exome sequencing; Massive parallel sequencing; Hereditary tumor syndromes
 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.

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Language(s): eng - English
 Dates: 2016-01-16
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1007/s10689-016-9870-z
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Title: Famillial Cancer
Source Genre: Journal
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Publ. Info: Springer
Pages: - Volume / Issue: 2016 Sequence Number: - Start / End Page: 1 - 8 Identifier: ISSN: 1389-9600 (print) 1573-7292 (online)