Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients.
In the majority of colorectal cancers (CRCs) under clinical suspicion for a hereditary cause, the disease-causing genetic factors are still to be discovered. To identify such genetic factors we stringently selected a discovery cohort of 41 CRC index patients with microsatellite-stable tumors. All patients were below 40 years of age at diagnosis and/or exhibited an overt family history. We employed genome-wide copy number profiling using high-resolution SNP arrays on germline DNA, which resulted in the identification of novel copy number variants (CNVs) in six patients (15%) encompassing, among others, the cadherin gene CDH18, the bone morphogenetic protein antagonist family gene GREM1, and the breakpoint cluster region gene BCR. In addition, two genomic deletions were encountered encompassing two microRNA genes, hsa-mir-491/KIAA1797 and hsa-mir-646/AK309218. None of these CNVs has previously been reported in relation to CRC predisposition in humans, nor were they encountered in large control cohorts (>1,600 unaffected individuals). Since several of these newly identified candidate genes may be functionally linked to CRC development, our results illustrate the potential of this approach for the identification of novel candidate genes involved in CRC predisposition.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Ramprasath
R
Venkatachalam
Eugène T P
ET
Verwiel
Eveline J
EJ
Kamping
Eveline
E
Hoenselaar
Heike
H
Görgens
Hans K
HK
Schackert
J Han J M
JH
van Krieken
Marjolijn J L
MJ
Ligtenberg
Nicoline
N
Hoogerbrugge
Ad Geurts
AG
van Kessel
Roland P
RP
Kuiper
D000328:Adult; D015820:Cadherins / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics; D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics
C104822:CDH18 protein, human; D015820:Cadherins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins