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Abstract
Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.
Highlights
Inherited susceptibility is responsible for,30% of all colorectal cancer (CRC) [1], high-penetrance germline mutations in APC, the mismatch repair (MMR) genes, MUTYH, SMAD4, BMPR1A (ALK3) and STK11 account for,6% of all CRC [2]
To elucidate a basis of this association we have systematically interrogated the 8q23 association signal through targeted resequencing, linkage disequilibrium (LD) mapping and functional analyses. He we show that a variant mapping to 8q23.3 may influence the transcriptional regulation of eukaryotic translation initiation factor 3, subunit H (EIF3H), MIM 603912
To understand the basis of this association we have compared the frequency of common genetic variants at 8q23 in,2,000 CRC cases and,2,000 healthy controls
Summary
Inherited susceptibility is responsible for ,30% of all CRC [1], high-penetrance germline mutations in APC, the mismatch repair (MMR) genes, MUTYH, SMAD4, BMPR1A (ALK3) and STK11 account for ,6% of all CRC [2]. Recent genome-wide association (GWA) studies we have conducted have vindicated a polygenic model of susceptibility to CRC based on the co-inheritance of multiple low-risk variants [3,4,5,6,7,8,9]. As the SNPs (or markers) genotyped during GWA studies are generally not themselves strong candidates for causality, enumeration of the genetic and functional basis at a specific locus poses a significant challenge. As demonstrated by recent studies of the 8q24 and 18q21 risk loci for CRC [10,11,12], dissecting the genetic and functional basis of associations identified by GWA studies can provide novel insights into cancer biology. To elucidate a basis of this association we have systematically interrogated the 8q23 association signal through targeted resequencing, linkage disequilibrium (LD) mapping and functional analyses
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