title: Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.
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.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.forename: Silvia
authors.initials: S
authors.lastname: Naranjo
authors.forename: Sanni E
authors.initials: SE
authors.lastname: Jalava
authors.forename: Philip
authors.initials: P
authors.lastname: Twiss
authors.forename: Yussanne
authors.initials: Y
authors.lastname: Ma
authors.forename: Bianca
authors.initials: B
authors.lastname: Olver
authors.forename: Amy
authors.initials: A
authors.lastname: Lloyd
authors.forename: Jayaram
authors.initials: J
authors.lastname: Vijayakrishnan
authors.forename: Mobshra
authors.initials: M
authors.lastname: Qureshi
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: M Eva
authors.initials: ME
authors.lastname: Alonso
authors.forename: Miguel
authors.initials: M
authors.lastname: Manzanares
authors.forename: Angela
authors.initials: A
authors.lastname: Gavilán
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: José Luis
authors.initials: JL
authors.lastname: Gómez-Skarmeta
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012307:Risk Factors
chemical_list: D039621:Eukaryotic Initiation Factor-3