Universität zu Köln

Kayser, Katrin, Degenhardt, Franziska, Holzapfel, Stefanie, Horpaopan, Sukanya, Peters, Sophia, Spier, Isabel, Morak, Monika, Vangala, Deepak, Rahner, Nils, von Knebel-Doeberitz, Magnus, Schackert, Hans K., Engel, Christoph ORCID: 0000-0002-7247-282X, Buettner, Reinhard, Wijnen, Juul, Doerks, Tobias, Bork, Peer, Moebus, Susanne, Herms, Stefan ORCID: 0000-0002-2786-8200, Fischer, Sascha, Hoffmann, Per, Aretz, Stefan ORCID: 0000-0002-5228-1890 and Steinke-Lange, Verena (2018). Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes. Int. J. Cancer, 143 (11). S. 2800 - 2814. HOBOKEN: WILEY. ISSN 1097-0215

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Abstract

In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kayser, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Degenhardt, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzapfel, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Horpaopan, Sukanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Peters, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Spier, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Morak, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Vangala, Deepak UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahner, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED von Knebel-Doeberitz, Magnus UNSPECIFIED UNSPECIFIED UNSPECIFIED Schackert, Hans K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Wijnen, Juul UNSPECIFIED UNSPECIFIED UNSPECIFIED Doerks, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Bork, Peer UNSPECIFIED UNSPECIFIED UNSPECIFIED Moebus, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Herms, Stefan UNSPECIFIED orcid.org/0000-0002-2786-8200 UNSPECIFIED Fischer, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Per UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED Steinke-Lange, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-163897
DOI:	10.1002/ijc.31725
Journal or Publication Title:	Int. J. Cancer
Volume:	143
Number:	11
Page Range:	S. 2800 - 2814
Date:	2018
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NONPOLYPOSIS COLORECTAL-CANCER; MISMATCH-REPAIR; CLINICAL-CRITERIA; MUTATIONS; GERMLINE; VARIANTS; MSH2; TRANSCRIPTION; PREDICTION; INVERSION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16389