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@ARTICLE{Kayser:141874,
author = {K. Kayser and F. Degenhardt and S. Holzapfel and S.
Horpaopan and S. Peters and I. Spier and M. Morak and D.
Vangala and N. Rahner and M. von Knebel-Doeberitz$^*$ and H.
K. Schackert and C. Engel and R. Büttner and J. Wijnen and
T. Doerks and P. Bork and S. Moebus and S. Herms and S.
Fischer and P. Hoffmann and S. Aretz and V. Steinke-Lange},
title = {{C}opy number variation analysis and targeted {NGS} in 77
families with suspected {L}ynch syndrome reveals novel
potential causative genes.},
journal = {International journal of cancer},
volume = {143},
number = {11},
issn = {0020-7136},
address = {Bognor Regis},
publisher = {Wiley-Liss},
reportid = {DKFZ-2018-02131},
pages = {2800 - 2813},
year = {2018},
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.},
cin = {G105},
ddc = {610},
cid = {I:(DE-He78)G105-20160331},
pnm = {317 - Translational cancer research (POF3-317)},
pid = {G:(DE-HGF)POF3-317},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29987844},
doi = {10.1002/ijc.31725},
url = {https://inrepo02.dkfz.de/record/141874},
}