Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.
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.
Pittman
Alan M
AM
Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.
Naranjo
Silvia
S
Jalava
Sanni E
SE
Twiss
Philip
P
Ma
Yussanne
Y
Olver
Bianca
B
Lloyd
Amy
A
Vijayakrishnan
Jayaram
J
Qureshi
Mobshra
M
Broderick
Peter
P
van Wezel
Tom
T
Morreau
Hans
H
Tuupanen
Sari
S
Aaltonen
Lauri A
LA
Alonso
M Eva
ME
Manzanares
Miguel
M
Gavilán
Angela
A
Visakorpi
Tapio
T
Gómez-Skarmeta
José Luis
JL
Houlston
Richard S
RS
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
D039621:Eukaryotic Initiation Factor-3