title: Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis.
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 (β-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.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Horpaopan
authors.forename: Isabel
authors.initials: I
authors.lastname: Spier
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Stefanie
authors.initials: S
authors.lastname: Holzapfel
authors.forename: Andreas
authors.initials: A
authors.lastname: Laner
authors.forename: Stefanie
authors.initials: S
authors.lastname: Vogt
authors.forename: Siegfried
authors.initials: S
authors.lastname: Uhlhaas
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Pasternack
authors.forename: Kathleen
authors.initials: K
authors.lastname: Keppler
authors.forename: Ronja
authors.initials: R
authors.lastname: Adam
authors.forename: Katrin
authors.initials: K
authors.lastname: Kayser
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.forename: Markus
authors.initials: M
authors.lastname: Draaken
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Alberto
authors.initials: A
authors.lastname: Perez-Bouza
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D056915:DNA Copy Number Variations; D045647:DNA Glycosylases / Q000235:genetics; D055106:Genome-Wide Association Study; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016547:Kinesins / Q000235:genetics; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; D050957:HSP110 Heat-Shock Proteins; C097205:HSPH1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C122169:TESK2 protein, human; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C583839:KIF26B protein, human; D016547:Kinesins
keywords: candidate genes; copy number variation; gastrointestinal polyposis; genetic cause; hereditary colorectal cancer; next generation sequencing; unexplained polyposis