Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1

Michela Biancolella, Barbara K. Fortini, Stephanie Tring, Sarah J. Plummer, Gustavo A. Mendoza-Fandino, Jaana Hartiala, Michael J. Hitchler, Chunli Yan, Fredrick R. Schumacher, David V. Conti, Christopher K. Edlund, Houtan Noushmehr, Simon G. Coetzee, Robert S. Bresalier, Dennis J. Ahnen, Elizabeth L. Barry, Benjamin P. Berman, Judd C. Rice, Gerhard A. Coetzee, Graham Casey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs3802842 is not the functional single-nucleotide polymorphism (SNP), but is in linkage disequilibrium (LD) with a functional SNP(s).We performed ChIP-seq for histone modifications in SW480 and HCT-116 CRC cells, andincorporated ChIP-seqandDNase I hypersensitivity data available through ENCODE within a 137-kbgenomic region containing rs3802842 on 11q23.1. We identified SNP rs10891246 in LD with rs3802842 that mapped within a bidirectional promoter region of genes C11orf92 and C11orf93. Following mutagenesis to the risk allele, the promoter demonstrated lower levels of reporter gene expression. A second SNP rs7130173 was identified in LD with rs3802842 that mapped to a candidate enhancer region, which showed strong unidirectional activity in both HCT-116 and SW480 CRC cells. The risk allele of rs7130173 demonstrated reduceden hancer activity compared with the common allele, and reduced nuclear protein binding affinity in electromobility shift assays compared with the common allele suggesting differential transcription factor (TF) binding. SNPs rs10891246 and rs7130173 are on the same haplotype, and expression quantitative trait loci (eQTL) analyses of neighboring genes implicate C11orf53, C11orf92 and C11orf93 as candidate target genes. These data imply that rs10891246 and rs7130173 are functional SNPs mapping to 11q23.1 and that C11orf53, C11orf92 and C11orf93 represent novel candidate target genes involved in CRC etiology.

Original languageAmerican English
Article numberddt584
Pages (from-to)2198-2209
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number8
DOIs
StatePublished - Apr 2014
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (R01 CA143237 to G.C.; U19 CA148107 to G.C. and G.A.C.; R01 CA059005 to J.B.). The scientific development and funding of this project was in part supported by the USC Norris Comprehensive Cancer Center Support Grant (NCI P30 CA014089) and by the CORECT consortium on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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