Horpaopan, Sukanya, Spier, Isabel, Zink, Alexander M., Altmueller, Janine, Holzapfel, Stefanie, Laner, Andreas, Vogt, Stefanie, Uhlhaas, Siegfried, Heilmann, Stefanie, Stienen, Dietlinde, Pasternack, Sandra M., Keppler, Kathleen, Adam, Ronja, Kayser, Katrin, Moebus, Susanne, Draaken, Markus ORCID: 0000-0002-4546-0786, Degenhardt, Franziska, Engels, Hartmut, Hofmann, Andrea, Noethen, Markus M., Steinke, Verena, Perez-Bouza, Alberto, Herms, Stefan ORCID: 0000-0002-2786-8200, Holinski-Feder, Elke, Froehlich, Holger, Thiele, Holger, Hoffmann, Per and Aretz, Stefan ORCID: 0000-0002-5228-1890 (2015). Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis. Int. J. Cancer, 136 (6). S. E578 - 12. HOBOKEN: WILEY. ISSN 1097-0215

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Abstract

To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant. What's new? So far, two genes have been implicated in the inheritance of adenomatous polyposis, a condition that leads to colorectal cancer: APC and MAP. But disturbances in these genes only account for about half of the disease cases. In this study, the authors sought that genetic basis by performing for the first time a genome-wide investigation into copy number variations among colorectal adenomatous polyposis patients. They identified a group of candidate genes that boost the risk of hereditary colorectal tumors; several patients had disruptions in multiple genes, suggesting that a simple lab test to evaluate risk might not be forthcoming.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Horpaopan, SukanyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spier, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zink, Alexander M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzapfel, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laner, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlhaas, SiegfriedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heilmann, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stienen, DietlindeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasternack, Sandra M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keppler, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, RonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kayser, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moebus, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Draaken, MarkusUNSPECIFIEDorcid.org/0000-0002-4546-0786UNSPECIFIED
Degenhardt, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engels, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinke, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Bouza, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herms, StefanUNSPECIFIEDorcid.org/0000-0002-2786-8200UNSPECIFIED
Holinski-Feder, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Froehlich, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aretz, StefanUNSPECIFIEDorcid.org/0000-0002-5228-1890UNSPECIFIED
URN: urn:nbn:de:hbz:38-404949
DOI: 10.1002/ijc.29215
Journal or Publication Title: Int. J. Cancer
Volume: 136
Number: 6
Page Range: S. E578 - 12
Date: 2015
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1097-0215
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COPY-NUMBER VARIATION; TUMOR-SUPPRESSOR GENES; CANCER SUSCEPTIBILITY; GERMLINE MUTATIONS; PROSTATE-CANCER; OVARIAN-CANCER; RARE VARIANTS; CELL-ADHESION; APC; PREDISPOSITIONMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40494

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